Apoptosis-inducing agent for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/682,603, filed Nov. 20, 2012, which is a divisional of U.S.application Ser. No. 12/689,133, filed Jan. 18, 2010, now U.S. Pat. No.8,338,466, issued Dec. 25, 2012, which claims the benefit of U.S.Provisional Application No. 61/145,611, filed Jan. 19, 2009, each ofwhich is incorporated herein by reference in its entirety.

SEQUENCE LISTING

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing, entitled 12655-125-999_SEQLIST.txt,of size 1,114 bytes, and created on Aug. 28, 2015.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of Bcl-2anti-apoptotic proteins, compositions containing the compounds, andmethods of treating diseases during which anti-apoptotic Bcl-2 proteinsare expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases.There is therefore an existing need in the therapeutic arts forcompounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, spleen cancer, and the like is described incommonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCTUS 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula I

wherein

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl,triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene;

wherein A¹ is unsubstituted or substituted with one or two or three orfour or five independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(N)C(O)R¹, C(O)NHR¹, C(O)N(R¹)₂,C(O)NHOH, C(O)NHOR¹, C(O)NHSO₂R¹, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHS(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHSO₂NHR¹, N(CH₃)SO₂N(CH₃)R¹, (O), NH₂, NO₂, N₃, OH, F, Cl, Br, I, CN,CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹,C(N)N(R¹)₂, CNOH, CNOCH₃, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,SR¹², S(O)R¹², SO₂R¹², C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹², NH₂,NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, C(O)OR³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene which is unfused or fused with benzene or heteroareneor R^(26A); R^(26A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(27A); R^(27A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), C(O)OR^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

-   -   wherein the moieties represented by R²⁶ and R²⁷ are        unsubstituted or substituted, (i.e., if Z^(1A) and Z^(2A) are        absent) or further unsubstituted or further substituted (i.e.,        if Z^(1A) and Z^(2A) are present) with one or more R⁴¹, OR⁴¹,        SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹, C(O)OR⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹,        NH₂, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹,        NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NH₂, NHC(O)NHR⁴¹,        NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NH₂,        C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹,        C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H, C(O)OH,        C(N)NH₂, C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,        NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, SR⁴⁶,S(O)R⁴⁶, SO₂R⁴⁶, C(O)R⁴⁶, C(O)OR⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

-   -   the moieties represented by R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are        independently unsubstituted or substituted with one or more        independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰,        C(O)R⁵⁰, C(O)OR⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂,        NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰,        NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂,        NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂,        C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂,        SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,        C(N)N(R⁵⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,        OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(53A); R^(53A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, C(O)OR⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵, NH₂,NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,C(O)OR⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷,NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂, NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂,C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂, C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷,C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷, SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶², OR⁶²,SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², C(O)OR⁶², OC(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(64A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶⁷, OR⁶⁷,SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, C(O)OR⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷, NH₂,NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, andR⁶⁷ are unsubstituted or substituted with one or more independentlyselected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸, C(O)R⁶⁸, C(O)OR⁶⁸, OC(O)R⁶⁸,OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸,NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸,NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸,C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂,SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I substituents;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁷³, OR⁷³,SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, C(O)OR⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂,NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted orsubstituted with one or more independently selected NH₂, C(O)NH₂,C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents.

In another embodiment of Formula (I),

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl,thiazolyl, thiadiazolyl, thienyl, triazolyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is heterocycloalkene;

wherein A¹ is unsubstituted or substituted with one or two or three orfour or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, CF₃;

R¹ is R², R³, R⁴ or R⁵;

R² is phenyl;

R³ is heteroaryl;

R⁴ is heterocycloalkyl;

R⁵ is alkyl, or alkenyl, each of which is unsubstituted or substitutedR⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, F, Cl, Br or I substituents;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is heterocycloalkyl;

R¹¹ is alkyl;

Z¹ is R²⁶;

Z² is R³⁰;

L¹ is a R³⁷;

R²⁶ is phenylene;

R³⁰ is heterocycloalkylene;

R³⁷ is R^(37A);

R^(37A) is alkylene, or alkenylene, each of which is unsubstituted orsubstituted with R^(37B);

R^(37B) is phenyl;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl;

R⁴⁰ is cycloalkyl, or cycloalkenyl;

wherein the moieties represented by R²⁶ and R²⁷ are unsubstituted orsubstituted with OR⁴¹;

R⁴¹ is R⁴², or R⁴³;

R⁴² is phenyl, which is unfused or fused with heteroarene;

R⁴³ is heteroaryl, which is unfused or fused with heteroarene;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, C(O)OR⁵⁷, F, Cl, Br or Isubstituents;

R⁵⁷ is R⁵⁸, or R⁶¹;

R⁵⁸ is phenyl;

R⁶¹ is alkyl; and

wherein the moieties represented by R⁵⁸, are unsubstituted orsubstituted with one or more independently selected F, Cl, Br or Isubstituents.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula II

wherein

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl,triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene;

wherein A¹ is unsubstituted or substituted with one or two or three orfour or five independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(N)C(O)R¹, C(O)NHR¹, C(O)N(R¹)₂,C(O)NHOH, C(O)NHOR¹, C(O)NHSO₂R¹, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHS(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHSO₂NHR¹, N(CH₃)SO₂N(CH₃)R¹, (O), NH₂, NO₂, N₃, OH, F, Cl, Br, I, CN,CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹,C(N)N(R¹)₂, CNOH, CNOCH₃, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,SR¹², S(O)R¹², SO₂R¹², C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹², NH₂,NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

wherein the moiety represented by R¹⁰¹ is H, R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹,SO₂R⁴¹, C(O)R⁴¹, C(O)OR⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂,NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹,NR⁴¹C(O)OR⁴¹, NHC(O)NH₂, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹,NR⁴¹C(O)N(R⁴¹)₂, C(O)NH₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹,C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, SR⁴⁶,S(O)R⁴⁶, SO₂R⁴⁶, C(O)R⁴⁶, C(O)OR⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

the moieties represented by R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted or substituted with one or moreindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,C(O)OR⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰,NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰,NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂,C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(53A); R^(53A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, C(O)OR⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵, NH₂,NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,C(O)OR⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷,NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂, NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂,C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂, C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷,C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷, SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶², OR⁶²,SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², C(O)OR⁶², OC(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(64A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶⁷, OR⁶⁷,SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, C(O)OR⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷, NH₂,NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, andR⁶⁷ are unsubstituted or substituted with one or more independentlyselected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸, C(O)R⁶⁸, C(O)OR⁶⁸, OC(O)R⁶⁸,OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸,NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸,NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸,C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂,SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I substituents;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁷³, OR⁷³,SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, C(O)OR⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂,NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted orsubstituted with one or more independently selected NH₂, C(O)NH₂,C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula III

wherein

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl,triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene;

wherein A¹ is unsubstituted or substituted with one or two or three orfour or five independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(N)C(O)R¹, C(O)NHR¹, C(O)N(R¹)₂,C(O)NHOH, C(O)NHOR¹, C(O)NHSO₂R¹, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHS(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHSO₂NHR¹, N(CH₃)SO₂N(CH₃)R¹, (O), NH₂, NO₂, N₃, OH, F, Cl, Br, I, CN,CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹,C(N)N(R¹)₂, CNOH, CNOCH₃, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,SR¹², S(O)R¹², SO₂R¹², C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹², NH₂,NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

wherein the moiety represented by R¹⁰¹ is H, R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹,SO₂R⁴¹, C(O)R⁴¹, C(O)OR⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂,NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹,NR⁴¹C(O)OR⁴¹, NHC(O)NH₂, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹,NR⁴¹C(O)N(R⁴¹)₂, C(O)NH₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹,C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, SR⁴⁶,S(O)R⁴⁶, SO₂R⁴⁶, C(O)R⁴⁶, C(O)OR⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶), NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)R⁴⁶, NR⁴⁶S(O)R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

the moieties represented by R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted or substituted with one or moreindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,C(O)OR⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰,NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰,NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂,C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(53A); R^(53A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, C(O)OR⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵, NH₂,NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,C(O)OR⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷,NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂, NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂,C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂, C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷,C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷, SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶², OR⁶²,SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², C(O)OR⁶², OC(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(6A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶⁷, OR⁶⁷,SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, C(O)OR⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷, NH₂,NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, andR⁶⁷ are unsubstituted or substituted with one or more independentlyselected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸, C(O)R⁶⁸, C(O)OR⁶⁸, OC(O)R⁶⁸,OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸,NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸,NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸,C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂,SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I substituents;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁷³, OR⁷³,SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, C(O)OR⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂,NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted orsubstituted with one or more independently selected NH₂, C(O)NH₂,C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents.

Still another embodiment pertains to compounds having Formula I, whichare

-   4-[4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidin-1-yl]benzamide;-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazin-1-yl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl    piperazin-1-yl)-N-([5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   N-{[(5Z)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-({5-[(benzoylamino)methyl]thien-2-yl}sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(morpholin-4-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)thien-3-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-fluoro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide;-   N-(1,3-benzothiazol-2-ylsulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(thien-2-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl})-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   ethyl    4-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;-   methyl    5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazol-5-yl)isoxazol-4-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-chloro-3-methylisothiazol-5-yl)sulfonyl]benzamide;-   N-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]thien-2-yl}sulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}benzamide;-   5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-nitro-5-piperidin-1-ylthien-2-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]thien-2-yl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitrothien-2-yl}sulfonyl)benzamide,-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(1,1-dioxidotetrahydrothien-3-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-phenoxybenzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   4-(4-({[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   tert-butyl    (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   tert-butyl    (2S)-2-{[(5-{[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;-   tert-butyl    (2S)-2-[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl)-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of thecompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount ofFormula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkyl” meansa straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₂-C₄ alkenyl” means an alkenyl group containing 2-4 carbon atoms.Representative examples of alkenyl include, but are not limited tobuta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term“C_(X)-C_(y) alkyl” means a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₁₀ alkyl”means a straight or branched chain, saturated hydrocarbon containing 2to 10 carbon atoms. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(X)-C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Examples of alkylene include, but are not limited to,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. Representative examples of alkynyl include, but arenot limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term “cycloalkylene” or cycloalkyl” or “cycloalkane” as used herein,means a monocyclic or bridged hydrocarbon ring system. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or twoalkylene bridges, each consisting of one, two, or three carbon atoms,each linking two non-adjacent carbon atoms of the ring system.Non-limiting examples of such bridged cycloalkyl ring systems includebicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). Themonocyclic and bridged cycloalkyl can be attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “cycloalkenylene,” or “cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbonatoms and zero heteroatoms. The four-membered ring systems have onedouble bond, the five- or six-membered ring systems have one or twodouble bonds, and the seven- or eight-membered ring systems have one,two, or three double bonds. Representative examples of monocycliccycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Themonocyclic cycloalkenyl ring may contain one or two alkylene bridges,each consisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bicyclic cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl,” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene,” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane,” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkanegroups include, but are not limited to, Representative examples ofheterocycloalkane groups include, but are not limited to, morpholinyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl,tetrahydrofuranyl, thiomorpholinyl, dioxanyl, tetrahydrothienyl,tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine,azepanyl, aziridinyl, diazepanyl, dithiolanyl, dithianyl,isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl,pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl, thiazolidinyl,thiomorpholinyl, trithianyl, and trithianyl.

The term “heterocycloalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkenegroups include, but are not limited to, tetrahydrooxocinyl,1,4,5,6-tetrahydropyridazinyl, 1,2,3,6-tetrahydropyridinyl,dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazolinyl,isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl,thiadiazolinyl, thiazolinyl, dihydro-1,3,4-thiadiazol-2-yl, andthiopyranyl.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃-spiroalkyl. C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₉-spiroalkyl and the like.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term, “spirocyclo,” as used herein, means two substituents on thesame carbon atom, that, together with the carbon atom to which they areattached, form a cycloalkane, heterocycloalkane, cycloalkene, orheterocycloalkene ring.

The term “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 1998, 63, 2758-2760 and E. L. Eliel, and S. H.Wilen. (1994) Stereochemistry of Organic Compounds. New York, N.Y.: JohnWiley & Sons, Inc.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs.” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmcokinetic profile or efficacy relative to the non-isotopiccompound.

Amides, Esters and Prodrugs

Prodrugs are derivatives of an active drug designed to ameliorate someidentified, undesirable physical or biological property. The physicalproperties are usually solubility (too much or not enough lipid oraqueous solubility) or stability related, while problematic biologicalproperties include too rapid metabolism or poor bioavailability whichitself may be related to a physicochemical property.

Prodrugs are usually prepared by: a) formation of ester, hemi esters,carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates,imines, Mannich bases, phosphates, phosphate esters, and enamines of theactive drug, b) functionalizing the drug with azo, glycoside, peptide,and ether functional groups, c) use of aminals, hemi-aminals, polymers,salts, complexes, phosphoramides, acetals, hemiacetals, and ketal formsof the drug. For example, see Andrejus Korolkovas's, “Essentials ofMedicinal Chemistry”, John Wiley-Interscience Publications, John Wileyand Sons, New York (1988), pp. 97-118, which is incorporated in itsentirety by reference herein.

Esters can be prepared from substrates of formula (I) containing eithera hydroxyl group or a carboxy group by general methods known to personsskilled in the art. The typical reactions of these compounds aresubstitutions replacing one of the heteroatoms by another atom, forexample:

Amides can be prepared from substrates of formula (I) containing eitheran amino group or a carboxy group in similar fashion. Esters can alsoreact with amines or ammonia to form amides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

In Schemes 2 and 3 above, R and R′ are independently substrates offormula (I), alkyl or hydrogen.

Suitable groups for A¹, L¹, Z^(1A), Z^(2A), Z¹, Z², and Z³ in compoundsof Formula (I) are independently selected. The described embodiments ofthe present invention may be combined. Such combination is contemplatedand within the scope of the present invention. For example, it iscontemplated that embodiments for any of A¹, L¹, Z^(1A), Z^(2A), Z¹, Z²,and Z³ can be combined with embodiments defined for any other of A¹, L¹,Z^(1A), Z^(2A), Z¹, Z², and Z³.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (I)

wherein

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl,triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene;

wherein A¹ is unsubstituted or substituted with one or two or three orfour or five independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(N)C(O)R¹, C(O)NHR¹, C(O)N(R¹)₂,C(O)NHOH, C(O)NHOR¹, C(O)NHSO₂R¹, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NRC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHS(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHSO₂NHR¹, N(CH₃)SO₂N(CH₃)R¹, (O), NH₂, NO₂, N₃, OH, F, Cl, Br, I, CN,CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹,C(N)N(R¹)₂, CNOH, CNOCH₃, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

Rx is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,SR¹², S(O)R¹², SO₂R¹², C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹², NH₂,NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, C(O)OR³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene which is unfused or fused with benzene or heteroareneor R^(26A); R^(26A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(27A); R^(27A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), C(O)OR^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are unsubstituted orsubstituted, (i.e., if Z^(1A) and Z^(2A) are absent) or furtherunsubstituted or further substituted (i.e., if Z^(1A) and Z^(2A) arepresent) with one or more R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,C(O)OR⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹,NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹,NHC(O)NH₂, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂,C(O)NH₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹,C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F. Cl, Br or I substituents;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, SR⁴⁶,S(O)R⁴⁶, SO₂R⁴⁶, C(O)R⁴⁶, C(O)OR⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶), NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

the moieties represented by R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted or substituted with one or moreindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,C(O)OR⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰,NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰,NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂,C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(53A); R^(53A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, C(O)OR⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵, NH₂,NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,C(O)OR⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷,NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂, NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂,C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂, C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷,C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷, SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₅₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶², OR⁶²,SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², C(O)OR⁶², OC(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(64A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶⁷, OR⁶⁷,SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, C(O)OR⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷, NH₂,NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, andR⁶⁷ are unsubstituted or substituted with one or more independentlyselected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸, C(O)R⁶⁸, C(O)OR⁶⁸, OC(O)R⁶⁸,OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸,NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸,NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸,C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂,SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I substituents;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl, or alkenyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁷³, OR⁷³,SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, C(O)OR⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂,NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³, C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and the moietiesrepresented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstituted or substituted withone or more independently selected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃,CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃,OCF₂CF₃, F, Cl, Br or I substituents.

In another embodiment of Formula (I),

A¹ is furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl,thiazolyl, thiadiazolyl, thienyl, triazolyl, heterocycloalkyl, orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene or A^(1A); A^(1A) is heterocycloalkene; wherein A¹ isunsubstituted or substituted with one or two or three or four or fiveindependently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂, C(N)C(O)R¹,C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, CF₃;

R¹ is R², R³, R⁴ or R⁵;

R² is phenyl;

R³ is heteroaryl;

R⁴ is heterocycloalkyl;

R⁵ is alkyl, or alkenyl, each of which is unsubstituted or substitutedR⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, F, Cl, Br or I substituents;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is heterocycloalkyl;

R¹¹ is alkyl;

Z¹ is R²⁶;

Z² is R³⁰;

L¹ is a R³⁷;

R²⁶ is phenylene;

R³⁰ is heterocycloalkylene;

R³⁷ is R^(37A);

R^(37A) is alkylene, or alkenylene, each of which is unsubstituted orsubstituted with R^(37B);

R^(37B) is phenyl;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl;

R⁴⁰ is cycloalkyl, or cycloalkenyl;

wherein the moieties represented by R²⁶ and R²⁷ are unsubstituted orsubstituted with OR⁴¹;

R⁴¹ is R⁴², or R⁴³;

R⁴² is phenyl, which is unfused or fused with heteroarene;

R⁴³ is heteroaryl, which is unfused or fused with heteroarene;

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ormore independently selected R⁵⁷, OR⁵⁷, C(O)OR⁵⁷, F, Cl, Br or Isubstituents;

R⁵⁷ is R⁵⁸, or R⁶¹;

R⁵⁸ is phenyl;

R⁶¹ is alkyl; and

wherein the moieties represented by R⁵⁸, are unsubstituted orsubstituted with one or more independently selected F, Cl, Br or Isubstituents.

In one embodiment of Formula (I), A¹ is furyl, imidazolyl, isothiazolyl,isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl,triazolyl, heterocycloalkyl, or heterocycloalkenyl; each of which isunfused or fused with benzene, heteroarene or A^(1A); and A^(1A) isheterocycloalkene. In another embodiment of Formula (I), A¹ is furyl. Inanother embodiment of Formula (I), A¹ is imidazolyl. In anotherembodiment of Formula (I), A¹ is isothiazolyl. In another embodiment ofFormula (I), A¹ is isoxazolyl. In another embodiment of Formula (I), A¹is pyrazolyl. In another embodiment of Formula (I), A¹ is pyrrolyl. Inanother embodiment of Formula (I), A¹ is thiazolyl. In anotherembodiment of Formula (I), A¹ is thiadiazolyl. In another embodiment ofFormula (I), A¹ is thienyl.

In another embodiment of Formula (I), A¹ is triazolyl. In anotherembodiment of Formula (I), A¹ is heterocycloalkyl. In another embodimentof Formula (I), A¹ is heterocycloalkenyl. In another embodiment ofFormula (I), A¹ is piperidinyl. In another embodiment of Formula (I), A¹is morpholinyl. In another embodiment of Formula (I), A¹ isdihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula (I), A¹is benzothien-2-yl. In another embodiment of Formula (I), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (I), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (I), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(I), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula (I),A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment ofFormula (I), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (I), A¹ is unsubstituted. In anotherembodiment of Formula (I), A¹ is substituted with one or two or three orfour or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (I), A¹ is unsubstituted. In anotherembodiment of Formula (I), A¹ is substituted with NHR¹. In anotherembodiment of Formula (I), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (I), A¹ is substituted with NHR¹. Inanother embodiment of Formula (I), A¹ is substituted with NR¹C(O)R¹. Inanother embodiment of Formula (I), A¹ is substituted with N(R¹)₂. Inanother embodiment of Formula (I), A¹ is substituted with C(N)C(O)R¹,and R¹. In another embodiment of Formula (I), A¹ is substituted withNHC(O)R¹, and R¹. In another embodiment of Formula (I), A¹ issubstituted with R¹. In another embodiment of Formula (I), A¹ issubstituted with two independently selected R¹. In another embodiment ofFormula (I), A¹ is substituted with Cl. In another embodiment of Formula(I), A¹ is substituted with CF₃. In another embodiment of Formula (I),A¹ is substituted with F. In another embodiment of Formula (I), A¹ issubstituted with three independently selected R¹, and C(O)OR¹. Inanother embodiment of Formula (I), A¹ is substituted R¹, and C(O)OR¹. Inanother embodiment of Formula (I), A¹ is substituted R¹, and Cl. Inanother embodiment of Formula (I), A¹ is substituted R¹, and Br. Inanother embodiment of Formula (I), A¹ is substituted with threeindependently selected R¹. In another embodiment of Formula (I), A¹ issubstituted with C(O)NHR¹. In another embodiment of Formula (I), A¹ issubstituted with two independently selected R¹, and Cl. In anotherembodiment of Formula (I), A¹ is substituted with R¹, and NO₂. Inanother embodiment of Formula (I), A¹ is substituted NHR¹, and NO₂. Inanother embodiment of Formula (I), A¹ is substituted with (O). Inanother embodiment of Formula (I), A¹ is substituted with OR¹.

In one embodiment of Formula (I), R¹ is phenyl. In another embodiment ofFormula (I), R¹ is pyrazolyl. In another embodiment of Formula (I), R¹is morpholinyl. In another embodiment of Formula (I), R¹ is isoxazolyl.In another embodiment of Formula (I), R¹ is piperidinyl. In anotherembodiment of Formula (I), R¹ is alkyl, which is unsubstituted. Inanother embodiment of Formula (I), R¹ is alkyl, which is substitutedwith one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (I), R⁷ is phenyl. In another embodiment ofFormula (I), R⁷ is methyl. In another embodiment of Formula (I), R⁷ isisopropyl. In another embodiment of Formula (I), R⁷ is pyrrolinyl. Inanother embodiment of Formula (I), R⁷ is morpholinyl. In anotherembodiment of Formula (I), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula I, whichare

-   4-[4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidin-1-yl]benzamide;-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazin-1-yl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   N-{[(5Z)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-({5-[(benzoylamino)methyl]thien-2-yl}sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(morpholin-4-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)thien-3-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-fluoro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide;-   N-(1,3-benzothiazol-2-ylsulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(thien-2-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   ethyl    4-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;-   methyl    5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazol-5-yl)isoxazol-4-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-chloro-3-methylisothiazol-5-yl)sulfonyl]benzamide;-   N-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]thien-2-yl}sulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}benzamide;-   5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-nitro-5-piperidin-1-ylthien-2-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]thien-2-yl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitrothien-2-yl}sulfonyl)benzamide;-   N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(1,1-dioxidotetrahydrothien-3-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl)}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-phenoxybenzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   4-{(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   tert-butyl (2S)-2-{[(5-{[4-(4    {[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   tert-butyl    (2S)-2-{[(5-{[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl)}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl)}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl)}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;-   tert-butyl    (2S)-2-{[(5-{([4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (II)

wherein R¹⁰¹ is H or is as described for substituents on R²⁶, and A¹ isas described in Formula (I).

In one embodiment of Formula (II), A¹ is furyl, imidazolyl,isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each ofwhich is unfused or fused with benzene, heteroarene or A^(1A); andA^(1A) is heterocycloalkene. In another embodiment of Formula (II), A¹is furyl. In another embodiment of Formula (II), A¹ is imidazolyl. Inanother embodiment of Formula (II), A¹ is isothiazolyl. In anotherembodiment of Formula (I), A¹ is isoxazolyl. In another embodiment ofFormula (II), A¹ is pyrazolyl. In another embodiment of Formula (II), A¹is pyrrolyl. In another embodiment of Formula (II), A¹ is thiazolyl. Inanother embodiment of Formula (II), A¹ is thiadiazolyl. In anotherembodiment of Formula (II), A¹ is thienyl.

In another embodiment of Formula (II), A¹ is triazolyl. In anotherembodiment of Formula (II), A¹ is heterocycloalkyl. In anotherembodiment of Formula (II), A¹ is heterocycloalkenyl. In anotherembodiment of Formula (II), A¹ is piperidinyl. In another embodiment ofFormula (II), A¹ is morpholinyl. In another embodiment of Formula (II),A¹ is dihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula(II), A¹ is benzothien-2-yl. In another embodiment of Formula (II), A¹is benzothiazol-2-yl. In another embodiment of Formula (II), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (II), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(I), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula (II),A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment ofFormula (II), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (II), A¹ is unsubstituted. In anotherembodiment of Formula (II), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (II), A¹ is unsubstituted. In anotherembodiment of Formula (II), A¹ is substituted with NHR¹. In anotherembodiment of Formula (II), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (II), A¹ is substituted with NHR¹. Inanother embodiment of Formula (I), A¹ is substituted with NR¹C(O)R¹. Inanother embodiment of Formula (II), A¹ is substituted with N(R¹)₂. Inanother embodiment of Formula (II), A¹ is substituted with C(N)C(O)R¹,and R¹. In another embodiment of Formula (II), A¹ is substituted withNHC(O)R¹, and R¹. In another embodiment of Formula (II), A¹ issubstituted with R¹. In another embodiment of Formula (II), A¹ issubstituted with two independently selected R¹. In another embodiment ofFormula (II), A¹ is substituted with Cl. In another embodiment ofFormula (II), A¹ is substituted with CF₃. In another embodiment ofFormula (II), A¹ is substituted with F. In another embodiment of Formula(II), A¹ is substituted with three independently selected R¹, andC(O)OR¹. In another embodiment of Formula (I), A¹ is substituted R¹, andC(O)OR¹. In another embodiment of Formula (II), A¹ is substituted R¹,and Cl. In another embodiment of Formula (II), A¹ is substituted R¹, andBr. In another embodiment of Formula (I), A¹ is substituted with threeindependently selected R¹. In another embodiment of Formula (II), A¹ issubstituted with C(O)NHR¹. In another embodiment of Formula (II), A¹ issubstituted with two independently selected R¹, and Cl. In anotherembodiment of Formula (II), A¹ is substituted with R¹, and NO₂. Inanother embodiment of Formula (II), A¹ is substituted NHR¹, and NO₂. Inanother embodiment of Formula (II), A¹ is substituted with (O). Inanother embodiment of Formula (II), A¹ is substituted with OR¹.

In one embodiment of Formula (II), R¹ is phenyl. In another embodimentof Formula (II), R¹ is pyrazolyl. In another embodiment of Formula (II),R¹ is morpholinyl. In another embodiment of Formula (II), R¹ isisoxazolyl. In another embodiment of Formula (II), R¹ is piperidinyl. Inanother embodiment of Formula (II), R¹ is alkyl, which is unsubstituted.In another embodiment of Formula (II), R¹ is alkyl, which is substitutedwith one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (II), R⁷ is phenyl. In another embodimentof Formula (II), R⁷ is methyl. In another embodiment of Formula (II), R⁷is isopropyl. In another embodiment of Formula (II), R⁷ is pyrrolinyl.In another embodiment of Formula (II), R⁷ is morpholinyl. In anotherembodiment of Formula (II), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula H, whichare

-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[(4-methyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   N-{[(5Z)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   N-({5-[(benzoylamino)methyl]thien-2-yl}sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(morpholin-4-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)thien-3-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-fluoro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide;-   N-(1,3-benzothiazol-2-ylsulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(thien-2-ylsulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl})-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   ethyl    4-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;-   methyl    5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazol-5-yl)isoxazol-4-yl]sulfonyl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-chloro-3-methylisothiazol-5-yl)sulfonyl]benzamide;-   N-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]thien-2-yl}sulfonyl)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}benzamide;-   5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-nitro-5-piperidin-1-ylthien-2-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-phenoxybenzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (III)

wherein R¹⁰¹ is H or is as described for substituents on R²⁶, and A¹ isas described in Formula (I).

In one embodiment of Formula (I), A¹ is furyl, imidazolyl, isothiazolyl,isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl,triazolyl, heterocycloalkyl, or heterocycloalkenyl; each of which isunfused or fused with benzene, heteroarene or A^(1A); and A^(1A) isheterocycloalkene. In another embodiment of Formula (III), A¹ is furyl.In another embodiment of Formula (III), A¹ is imidazolyl. In anotherembodiment of Formula (III), A¹ is isothiazolyl. In another embodimentof Formula (III), A¹ is isoxazolyl. In another embodiment of Formula(III), A¹ is pyrazolyl. In another embodiment of Formula (III), A¹ ispyrrolyl. In another embodiment of Formula (III), A¹ is thiazolyl. Inanother embodiment of Formula (III), A¹ is thiadiazolyl. In anotherembodiment of Formula (III), A¹ is thienyl.

In another embodiment of Formula (III), A¹ is triazolyl. In anotherembodiment of Formula (III), A¹ is heterocycloalkyl. In anotherembodiment of Formula (III), A¹ is heterocycloalkenyl. In anotherembodiment of Formula (III), A¹ is piperidinyl. In another embodiment ofFormula (III), A¹ is morpholinyl. In another embodiment of Formula(III), A¹ is dihydro-1,3,4-thiadiazol-2-yl. In another embodiment ofFormula (III), A¹ is benzothien-2-yl. In another embodiment of Formula(II), A¹ is benzothiazol-2-yl. In another embodiment of Formula (III),A¹ is benzothiazol-2-yl. In another embodiment of Formula (III), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(III), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula(III), A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodimentof Formula (III), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (III), A¹ is unsubstituted. In anotherembodiment of Formula (III), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (III), A¹ is unsubstituted. In anotherembodiment of Formula (III), A¹ is substituted with NHR¹. In anotherembodiment of Formula (III), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (III), A¹ is substituted with NHR¹. Inanother embodiment of Formula (III), A¹ is substituted with NR¹C(O)R¹.In another embodiment of Formula (III), A¹ is substituted with N(R¹)₂.In another embodiment of Formula (III), A¹ is substituted withC(N)C(O)R¹, and R¹. In another embodiment of Formula (III), A¹ issubstituted with NHC(O)R¹, and R¹. In another embodiment of Formula(III), A¹ is substituted with R¹. In another embodiment of Formula(III), A¹ is substituted with two independently selected R¹. In anotherembodiment of Formula (III), A¹ is substituted with Cl. In anotherembodiment of Formula (III), A¹ is substituted with CF₃. In anotherembodiment of Formula (III), A¹ is substituted with F. In anotherembodiment of Formula (III), A¹ is substituted with three independentlyselected R¹, and C(O)OR¹. In another embodiment of Formula (III), A¹ issubstituted R¹, and C(O)OR¹. In another embodiment of Formula (III), A¹is substituted R¹, and Cl. In another embodiment of Formula (III), A¹ issubstituted R¹, and Br. In another embodiment of Formula (III), A¹ issubstituted with three independently selected R¹. In another embodimentof Formula (III), A¹ is substituted with C(O)NHR¹. In another embodimentof Formula (II), A¹ is substituted with two independently selected R¹,and Cl. In another embodiment of Formula (III), A¹ is substituted withR¹, and NO₂. In another embodiment of Formula (III), A¹ is substitutedNHR¹, and NO₂. In another embodiment of Formula (II), A¹ is substitutedwith (O). In another embodiment of Formula (III), A¹ is substituted withOR¹.

In one embodiment of Formula (III), R¹ is phenyl. In another embodimentof Formula (III), R¹ is pyrazolyl. In another embodiment of Formula(III), R¹ is morpholinyl. In another embodiment of Formula (III), R¹ isisoxazolyl. In another embodiment of Formula (III), R¹ is piperidinyl.In another embodiment of Formula (III), R¹ is alkyl, which isunsubstituted. In another embodiment of Formula (III), R¹ is alkyl,which is substituted with one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (III), R⁷ is phenyl. In another embodimentof Formula (III), R⁷ is methyl. In another embodiment of Formula (III),R⁷ is isopropyl. In another embodiment of Formula (III), R⁷ ispyrrolinyl. In another embodiment of Formula (III), R⁷ is morpholinyl.In another embodiment of Formula (III), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula II, whichare

-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]thien-2-yl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitrothien-2-yl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide;-   tert-butyl    (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   tert-butyl    (2S)-2-{[(5-[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl)-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;-   tert-butyl    (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (IV)

wherein one R¹⁰² is the point of attachment to the indole, and theremainder are H or are as described for substituents on R⁴², and A¹ andZ³ are as described in Formula (I).

In one embodiment of Formula (IV), A¹ is furyl, imidazolyl,isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each ofwhich is unfused or fused with benzene, heteroarene or A^(1A); andA^(1A) is heterocycloalkene. In another embodiment of Formula (IV), A¹is furyl. In another embodiment of Formula (IV), A¹ is imidazolyl. Inanother embodiment of Formula (IV), A¹ is isothiazolyl. In anotherembodiment of Formula (IV), A¹ is isoxazolyl. In another embodiment ofFormula (IV), A¹ is pyrazolyl. In another embodiment of Formula (IV), A¹is pyrrolyl. In another embodiment of Formula (IV), A¹ is thiazolyl. Inanother embodiment of Formula (IV), A¹ is thiadiazolyl. In anotherembodiment of Formula (IV), A¹ is thienyl.

In another embodiment of Formula (IV), A¹ is triazolyl. In anotherembodiment of Formula (IV), A¹ is heterocycloalkyl. In anotherembodiment of Formula (IV), A¹ is heterocycloalkenyl. In anotherembodiment of Formula (IV), A¹ is piperidinyl. In another embodiment ofFormula (IV), A¹ is morpholinyl. In another embodiment of Formula (IV),A¹ is dihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula(IV), A¹ is benzothien-2-yl. In another embodiment of Formula (IV), A¹is benzothiazol-2-yl. In another embodiment of Formula (IV), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (IV), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(IV), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula (IV),A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment ofFormula (V), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (IV), A¹ is unsubstituted. In anotherembodiment of Formula (IV), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (IV), A¹ is unsubstituted. In anotherembodiment of Formula (IV), A¹ is substituted with NHR¹. In anotherembodiment of Formula (IV), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (IV), A¹ is substituted with NHR¹. Inanother embodiment of Formula (IV), A¹ is substituted with NR¹C(O)R¹. Inanother embodiment of Formula (IV), A¹ is substituted with N(R¹)₂. Inanother embodiment of Formula (IV), A¹ is substituted with C(N)C(O)R¹,and R¹. In another embodiment of Formula (IV), A¹ is substituted withNHC(O)R¹, and R¹. In another embodiment of Formula (IV), A¹ issubstituted with R¹. In another embodiment of Formula (IV), A¹ issubstituted with two independently selected R¹. In another embodiment ofFormula (IV), A¹ is substituted with Cl. In another embodiment ofFormula (IV), A¹ is substituted with CF₃. In another embodiment ofFormula (V), A¹ is substituted with F. In another embodiment of Formula(IV), A¹ is substituted with three independently selected R¹, andC(O)OR¹. In another embodiment of Formula (IV), A¹ is substituted R¹,and C(O)OR¹. In another embodiment of Formula (V), A¹ is substituted R¹,and Cl. In another embodiment of Formula (IV), A¹ is substituted R¹, andBr. In another embodiment of Formula (IV), A¹ is substituted with threeindependently selected R¹. In another embodiment of Formula (IV), A¹ issubstituted with C(O)NHR¹. In another embodiment of Formula (IV), A¹ issubstituted with two independently selected R¹, and Cl. In anotherembodiment of Formula (IV), A¹ is substituted with R¹, and NO₂. Inanother embodiment of Formula (IV), A¹ is substituted NHR¹, and NO₂. Inanother embodiment of Formula (IV), A¹ is substituted with (O). Inanother embodiment of Formula (IV), A¹ is substituted with OR¹.

In one embodiment of Formula (IV), R¹ is phenyl. In another embodimentof Formula (IV), R¹ is pyrazolyl. In another embodiment of Formula (IV),R¹ is morpholinyl. In another embodiment of Formula (IV), R¹ isisoxazolyl. In another embodiment of Formula (IV), R¹ is piperidinyl. Inanother embodiment of Formula (IV), R¹ is alkyl, which is unsubstituted.In another embodiment of Formula (IV), R¹ is alkyl, which is substitutedwith one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (IV), R⁷ is phenyl. In another embodimentof Formula (IV), R⁷ is methyl. In another embodiment of Formula (IV), R⁷is isopropyl. In another embodiment of Formula (IV), R⁷ is pyrrolinyl.In another embodiment of Formula (IV), R⁷ is morpholinyl. In anotherembodiment of Formula (IV), R⁷ is tetrahydropyranyl.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (V)

wherein one R¹⁰² is the point of attachment to the indazole, and theremainder are H or are as described for substituents on R⁴², and A¹ andZ³ are as described in Formula (I).

In one embodiment of Formula (V), A¹ is furyl, imidazolyl, isothiazolyl,isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl,triazolyl, heterocycloalkyl, or heterocycloalkenyl; each of which isunfused or fused with benzene, heteroarene or A^(1A); and A^(1A) isheterocycloalkene. In another embodiment of Formula (V), A¹ is furyl. Inanother embodiment of Formula (V), A¹ is imidazolyl. In anotherembodiment of Formula (V), A¹ is isothiazolyl. In another embodiment ofFormula (V), A¹ is isoxazolyl. In another embodiment of Formula (V), A¹is pyrazolyl. In another embodiment of Formula (V), A¹ is pyrrolyl. Inanother embodiment of Formula (V), A¹ is thiazolyl. In anotherembodiment of Formula (V), A¹ is thiadiazolyl. In another embodiment ofFormula (V), A¹ is thienyl.

In another embodiment of Formula (V), A¹ is triazolyl.

heterocycloalkenyl. In another embodiment of Formula (V), A¹ ispiperidinyl. In another embodiment of Formula (V), A¹ is morpholinyl. Inanother embodiment of Formula (V), A¹ is dihydro-1,3,4-thiadiazol-2-yl.In another embodiment of Formula (V), A¹ is benzothien-2-yl. In anotherembodiment of Formula (V), A¹ is benzothiazol-2-yl. In anotherembodiment of Formula (V), A¹ is benzothiazol-2-yl. In anotherembodiment of Formula (V), A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl.In another embodiment of Formula (V), A¹ is tetrahydrothien-3-yl. Inanother embodiment of Formula (V), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(V), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (V), A¹ is unsubstituted. In anotherembodiment of Formula (V), A¹ is substituted with one or two or three orfour or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (V), A¹ is unsubstituted. In anotherembodiment of Formula (V), A¹ is substituted with NHR¹. In anotherembodiment of Formula (V), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (V), A¹ is substituted with NHR¹. Inanother embodiment of Formula (V), A¹ is substituted with NR¹C(O)R¹. Inanother embodiment of Formula (V), A¹ is substituted with N(R¹)₂. Inanother embodiment of Formula (V), A¹ is substituted with C(N)C(O)R¹,and R¹. In another embodiment of Formula (V), A¹ is substituted withNHC(O)R¹, and R¹. In another embodiment of Formula (V), A¹ issubstituted with R¹. In another embodiment of Formula (V), A¹ issubstituted with two independently selected R¹. In another embodiment ofFormula (V), A¹ is substituted with Cl. In another embodiment of Formula(V), A¹ is substituted with CF₃. In another embodiment of Formula (V),A¹ is substituted with F. In another embodiment of Formula (V), A¹ issubstituted with three independently selected R¹, and C(O)OR¹. Inanother embodiment of Formula (V), A¹ is substituted R¹, and C(O)OR¹. Inanother embodiment of Formula (V), A¹ is substituted R¹, and Cl. Inanother embodiment of Formula (V), A¹ is substituted R¹, and Br. Inanother embodiment of Formula (V), A¹ is substituted with threeindependently selected R¹. In another embodiment of Formula (V), A¹ issubstituted with C(O)NHR¹. In another embodiment of Formula (V), A¹ issubstituted with two independently selected R¹, and Cl. In anotherembodiment of Formula (V), A¹ is substituted with R¹, and NO₂. Inanother embodiment of Formula (V), A¹ is substituted NHR¹, and NO₂. Inanother embodiment of Formula (V), A¹ is substituted with (O). Inanother embodiment of Formula (V), A¹ is substituted with OR¹.

In one embodiment of Formula (V), R¹ is phenyl. In another embodiment ofFormula (V), R¹ is pyrazolyl. In another embodiment of Formula (V), R¹is morpholinyl. In another embodiment of Formula (V), R¹ is isoxazolyl.In another embodiment of Formula (V), R¹ is piperidinyl. In anotherembodiment of Formula (V), R¹ is alkyl, which is unsubstituted. Inanother embodiment of Formula (V), R¹ is alkyl, which is substitutedwith one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (V), R⁷ is phenyl. In another embodiment ofFormula (V), R⁷ is methyl. In another embodiment of Formula (V), R⁷ isisopropyl. In another embodiment of Formula (V), R⁷ is pyrrolinyl. Inanother embodiment of Formula (V), R⁷ is morpholinyl. In anotherembodiment of Formula (V), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula V, whichare

-   tert-butyl    (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (VI)

wherein one R¹⁰² is the point of attachment to the benzimidazole, andthe remainder are H or are as described for substituents on R⁴², and A¹and Z³ are as described in Formula (I).

In one embodiment of Formula (VI), A¹ is furyl, imidazolyl,isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each ofwhich is unfused or fused with benzene, heteroarene or A^(1A); andA^(1A) is heterocycloalkene. In another embodiment of Formula (VI), A¹is furyl. In another embodiment of Formula (VI), A¹ is imidazolyl. Inanother embodiment of Formula (VI), A¹ is isothiazolyl. In anotherembodiment of Formula (VI), A¹ is isoxazolyl. In another embodiment ofFormula (VI), A¹ is pyrazolyl. In another embodiment of Formula (VI), A¹is pyrrolyl. In another embodiment of Formula (VI), A¹ is thiazolyl. Inanother embodiment of Formula (VI), A¹ is thiadiazolyl. In anotherembodiment of Formula (VI), A¹ is thienyl. In another embodiment ofFormula (VI), A¹ is triazolyl. In another embodiment of Formula (VI), A¹is heterocycloalkyl. In another embodiment of Formula (VI), A¹ isheterocycloalkenyl. In another embodiment of Formula (VI), A¹ ispiperidinyl. In another embodiment of Formula (VI), A¹ is morpholinyl.In another embodiment of Formula (VI), A¹ isdihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula (VI), A¹is benzothien-2-yl. In another embodiment of Formula (VI), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VI), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VI), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(VI), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula (VI),A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment ofFormula (VI), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (VI), A¹ is unsubstituted. In anotherembodiment of Formula (VI), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (VI), A¹ is unsubstituted. In anotherembodiment of Formula (VI), A¹ is substituted with NHR¹. In anotherembodiment of Formula (VI), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (VI), A¹ is substituted with NHR¹. Inanother embodiment of Formula (VI), A¹ is substituted with NR¹C(O)R¹. Inanother embodiment of Formula (VI), A¹ is substituted with N(R¹). Inanother embodiment of Formula (VI), A¹ is substituted with C(N)C(O)R¹,and R¹. In another embodiment of Formula (VI), A¹ is substituted withNHC(O)R¹, and R¹. In another embodiment of Formula (VI), A¹ issubstituted with R¹. In another embodiment of Formula (VI), A¹ issubstituted with two independently selected R¹. In another embodiment ofFormula (VI), A¹ is substituted with Cl. In another embodiment ofFormula (VI), A¹ is substituted with CF₃. In another embodiment ofFormula (VI), A¹ is substituted with F. In another embodiment of Formula(VI), A¹ is substituted with three independently selected R¹, andC(O)OR¹. In another embodiment of Formula (VI), A¹ is substituted R¹,and C(O)OR¹. In another embodiment of Formula (VI), A¹ is substitutedR¹, and Cl. In another embodiment of Formula (VI), A¹ is substituted R¹,and Br. In another embodiment of Formula (VI), A¹ is substituted withthree independently selected R¹. In another embodiment of Formula (VI),A¹ is substituted with C(O)NHR¹. In another embodiment of Formula (VI),A¹ is substituted with two independently selected R¹, and Cl. In anotherembodiment of Formula (VI), A¹ is substituted with R¹, and NO₂. Inanother embodiment of Formula (VI), A¹ is substituted NHR¹, and NO₂. Inanother embodiment of Formula (VI), A¹ is substituted with (O). Inanother embodiment of Formula (VI), A¹ is substituted with OR¹.

In one embodiment of Formula (VI), R¹ is phenyl. In another embodimentof Formula (VI), R¹ is pyrazolyl. In another embodiment of Formula (VI),R¹ is morpholinyl. In another embodiment of Formula (VI), R¹ isisoxazolyl. In another embodiment of Formula (VI), R¹ is piperidinyl. Inanother embodiment of Formula (VI), R¹ is alkyl, which is unsubstituted.In another embodiment of Formula (VI), R¹ is alkyl, which is substitutedwith one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (VI), R⁷ is phenyl. In another embodimentof Formula (VI), R⁷ is methyl. In another embodiment of Formula (VI), R⁷is isopropyl. In another embodiment of Formula (VI), R⁷ is pyrrolinyl.In another embodiment of Formula (VI), R⁷ is morpholinyl. In anotherembodiment of Formula (VI), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula VI, whichare

-   tert-butyl    (2S)-2-{[(5-[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl)-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (VII)

wherein one R¹⁰² is the point of attachment to the pyridine, and theremainder are H or are as described for substituents on R⁴², and A¹ andZ³ are as described in Formula (I).

In one embodiment of Formula (VII), A¹ is furyl, imidazolyl,isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each ofwhich is unfused or fused with benzene, heteroarene or A^(1A); andA^(1A) is heterocycloalkene. In another embodiment of Formula (VII), A¹is furyl. In another embodiment of Formula (VII), A¹ is imidazolyl. Inanother embodiment of Formula (VII), A¹ is isothiazolyl. In anotherembodiment of Formula (VII), A¹ is isoxazolyl. In another embodiment ofFormula (VII), A¹ is pyrazolyl. In another embodiment of Formula (VII),A¹ is pyrrolyl. In another embodiment of Formula (VII), A¹ is thiazolyl.In another embodiment of Formula (VII), A¹ is thiadiazolyl. In anotherembodiment of Formula (VII), A¹ is thienyl. In another embodiment ofFormula (VII), A¹ is triazolyl. In another embodiment of Formula (VII),A¹ is heterocycloalkyl. In another embodiment of Formula (VII), A¹ isheterocycloalkenyl. In another embodiment of Formula (VII), A¹ ispiperidinyl. In another embodiment of Formula (VII), A¹ is morpholinyl.In another embodiment of Formula (VII), A¹ isdihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula (VII),A¹ is benzothien-2-yl. In another embodiment of Formula (VII), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VII), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VII), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(VII), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula(VII), A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodimentof Formula (VII), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (VII), A¹ is unsubstituted. In anotherembodiment of Formula (VII), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (VII), A¹ is unsubstituted. In anotherembodiment of Formula (VII), A¹ is substituted with NHR¹. In anotherembodiment of Formula (VII), A¹ is substituted with NHR¹, and NO₂. Inanother embodiment of Formula (VII), A¹ is substituted with NHR¹. Inanother embodiment of Formula (VII), A¹ is substituted with NR¹C(O)R¹.In another embodiment of Formula (VII), A¹ is substituted with N(R¹)₂.In another embodiment of Formula (VII), A¹ is substituted withC(N)C(O)R¹, and R¹. In another embodiment of Formula (VII), A¹ issubstituted with NHC(O)R¹, and R¹. In another embodiment of Formula(VII), A¹ is substituted with R¹. In another embodiment of Formula(VII), A¹ is substituted with two independently selected R¹. In anotherembodiment of Formula (VII), A¹ is substituted with Cl. In anotherembodiment of Formula (VII), A¹ is substituted with CF₃. In anotherembodiment of Formula (VII), A¹ is substituted with F. In anotherembodiment of Formula (VII), A¹ is substituted with three independentlyselected R¹, and C(O)OR¹. In another embodiment of Formula (VII), A¹ issubstituted R¹, and C(O)OR¹. In another embodiment of Formula (VII), A¹is substituted R¹, and Cl. In another embodiment of Formula (VII), A¹ issubstituted R¹, and Br. In another embodiment of Formula (VII), A¹ issubstituted with three independently selected R¹. In another embodimentof Formula (VII), A¹ is substituted with C(O)NHR¹. In another embodimentof Formula (VII), A¹ is substituted with two independently selected R¹,and Cl. In another embodiment of Formula (VII), A¹ is substituted withR¹, and NO₂. In another embodiment of Formula (VII), A¹ is substitutedNHR¹, and NO₂. In another embodiment of Formula (VII), A¹ is substitutedwith (O). In another embodiment of Formula (VII), A¹ is substituted withOR¹.

In one embodiment of Formula (VII), R¹ is phenyl. In another embodimentof Formula (VII), R¹ is pyrazolyl. In another embodiment of Formula(VII), R¹ is morpholinyl. In another embodiment of Formula (VII), R¹ isisoxazolyl. In another embodiment of Formula (VII), R¹ is piperidinyl.In another embodiment of Formula (VII), R¹ is alkyl, which isunsubstituted. In another embodiment of Formula (VII), R¹ is alkyl,which is substituted with one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (VII), R⁷ is phenyl. In another embodimentof Formula (VII), R⁷ is methyl. In another embodiment of Formula (VII),R⁷ is isopropyl. In another embodiment of Formula (VII), R⁷ ispyrrolinyl. In another embodiment of Formula (VII), R⁷ is morpholinyl.In another embodiment of Formula (VII), R⁷ is tetrahydropyranyl.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs, metabolites, or salts ofprodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (VIII)

wherein each R¹⁰² are independently H or are as described forsubstituents on R⁴², and A¹ and Z³ are as described in Formula (I).

In one embodiment of Formula (VIII), A¹ is furyl, imidazolyl,isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,thienyl, triazolyl, heterocycloalkyl, or heterocycloalkenyl; each ofwhich is unfused or fused with benzene, heteroarene or A^(1A); andA^(1A) is heterocycloalkene. In another embodiment of Formula (VIII), A¹is furyl. In another embodiment of Formula (VIII), A¹ is imidazolyl. Inanother embodiment of Formula (VIII), A¹ is isothiazolyl. In anotherembodiment of Formula (VIII), A¹ is isoxazolyl. In another embodiment ofFormula (VIII), A¹ is pyrazolyl. In another embodiment of Formula(VIII), A¹ is pyrrolyl. In another embodiment of Formula (VIII), A¹ isthiazolyl. In another embodiment of Formula (VIII), A¹ is thiadiazolyl.In another embodiment of Formula (VIII), A¹ is thienyl. In anotherembodiment of Formula (VIII), A¹ is triazolyl. In another embodiment ofFormula (VIII), A¹ is heterocycloalkyl. In another embodiment of Formula(VIII), A¹ is heterocycloalkenyl. In another embodiment of Formula(VIII), A¹ is piperidinyl. In another embodiment of Formula (VIII), A¹is morpholinyl. In another embodiment of Formula (VIII), A¹ isdihydro-1,3,4-thiadiazol-2-yl. In another embodiment of Formula (VIII),A¹ is benzothien-2-yl. In another embodiment of Formula (VIII), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VIII), A¹ isbenzothiazol-2-yl. In another embodiment of Formula (VIII), A¹ is[1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In another embodiment of Formula(VIII), A¹ is tetrahydrothien-3-yl. In another embodiment of Formula(VIII), A¹ is [1,2,4]triazolo[1,5-a]pyrimidin-2-yl. In anotherembodiment of Formula (VIII), A¹ is imidazo[2,1-b][1,3]thiazol-5-yl.

In one embodiment of Formula (VIII), A¹ is unsubstituted. In anotherembodiment of Formula (VIII), A¹ is substituted with one or two or threeor four or five independently selected R¹, OR¹, C(O)OR¹, NHR¹, N(R¹)₂,C(N)C(O)R¹, C(O)NHR¹, NHC(O)R¹, NR¹C(O)R¹, (O), NO₂, F, Cl, Br, I, orCF₃. In one embodiment of Formula (VIII), A¹ is unsubstituted. Inanother embodiment of Formula (VIII), A¹ is substituted with NHR¹. Inanother embodiment of Formula (VIII), A¹ is substituted with NHR¹, andNO₂. In another embodiment of Formula (VIII), A¹ is substituted withNHR¹. In another embodiment of Formula (VIII), A¹ is substituted withNR¹C(O)R¹. In another embodiment of Formula (VIII), A¹ is substitutedwith N(R¹)₂. In another embodiment of Formula (VIII), A¹ is substitutedwith C(N)C(O)R¹, and R¹. In another embodiment of Formula (VIII), A¹ issubstituted with NHC(O)R¹, and R¹. In another embodiment of Formula(VIII), A¹ is substituted with R¹. In another embodiment of Formula(VIII), A¹ is substituted with two independently selected R¹. In anotherembodiment of Formula (VIII), A¹ is substituted with Cl. In anotherembodiment of Formula (VIII), A¹ is substituted with CF₃. In anotherembodiment of Formula (VIII), A¹ is substituted with F. In anotherembodiment of Formula (VIII), A¹ is substituted with three independentlyselected R¹, and C(O)OR¹. In another embodiment of Formula (VIII), A¹ issubstituted R¹, and C(O)OR¹. In another embodiment of Formula (VIII), A¹is substituted R¹, and Cl. In another embodiment of Formula (VIII), A¹is substituted R¹, and Br. In another embodiment of Formula (VIII), A¹is substituted with three independently selected R¹. In anotherembodiment of Formula (VIII), A¹ is substituted with C(O)NHR¹. Inanother embodiment of Formula (VIII), A¹ is substituted with twoindependently selected R¹, and Cl. In another embodiment of Formula(VIII), A¹ is substituted with R¹, and NO₂. In another embodiment ofFormula (VIII), A¹ is substituted NHR¹, and NO₂. In another embodimentof Formula (VIII), A¹ is substituted with (O). In another embodiment ofFormula (VIII), A¹ is substituted with OR¹.

In one embodiment of Formula (VIII), R¹ is phenyl. In another embodimentof Formula (VIII), R¹ is pyrazolyl. In another embodiment of Formula(VIII), R¹ is morpholinyl. In another embodiment of Formula (VIII), R¹is isoxazolyl. In another embodiment of Formula (VIII), R¹ ispiperidinyl. In another embodiment of Formula (VIII), R¹ is alkyl, whichis unsubstituted. In another embodiment of Formula (VIII), R¹ is alkyl,which is substituted with one or more R⁷, SR⁷, N(R⁷)₂, NHC(O)R⁷, or Cl.

In one embodiment of Formula (VIII), R⁷ is phenyl. In another embodimentof Formula (VIII), R⁷ is methyl. In another embodiment of Formula(VIII), R⁷ is isopropyl. In another embodiment of Formula (VIII), R⁷ ispyrrolinyl. In another embodiment of Formula (VIII), R⁷ is morpholinyl.In another embodiment of Formula (VIII), R⁷ is tetrahydropyranyl.

Still another embodiment pertains to compounds having Formula VIII,which are

-   tert-butyl    (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl)    sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.    Pharmaceutical Compositions, Combination Therapies, Methods of    Treatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (I) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds having Formula (I) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds having Formula (I) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (I) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered parenterally include,for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil,U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents. BiTEantibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN®(trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010.CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib). MG 132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUNL® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG 1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine. FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin). AMPLIGEN® ® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine). GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase. PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as bindersto and inhibitors of anti-apoptotic Bcl-2 proteins was performed usingthe Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 μmol preloaded Wangresin/vessel on an ABI 433A peptide synthesizer using 250 μmol scaleFastmoc™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyltrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with dichloromethaneand kept wet. 150 mL of 95:4:1dichloromethane:triisopropylsilane:trifluoroacetic acid was flowedthrough the resin bed over 30 minutes. The mixture turned deep yellowthen faded to pale yellow. 100 mL of N,N-dimethylformamide was flowedthrough the bed over 15 minutes. The resin was then washed thrice withN,N-dimethylformamide and filtered. Ninhydrin tests showed a strongsignal for primary amine.

Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1%DIEA/N,N-dimethylformamide and stirred or shaken at ambient temperatureovernight. When complete, the resin was drained, washed thrice withN,N-dimethylformamide, thrice with (1×DCM and 1× methanol) and dried toprovide an orange resin that was negative by ninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 Å pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D CHEMSTATION software version A.03.04(Hewlett-Packard. Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 μm particles with a 120 Å pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

F-Bak: Peptide Probe Acetyl-GQVGRQLAIIGDK(6-FAM)INR-NH₂ (SEQ ID NO:1)

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1[(M+H)⁺].

Alternative Synthesis of Peptide Probe F-Bak:Acetyl-GQVGRQLAIIGDK(6-FAM)INR-NH₂ (SEQ ID NO:1)

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running FASTMOC™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer 6carboxyfluorescein-NHS was reacted with the lysine side-chain in 1% DIEAin N,N-dimethylformamide and confirmed complete by ninhydrin testing.The peptide was cleaved from the resin and side-chains deprotected bytreating with 80:5:5:5:2.5:2.5TFA/water/phenol/thioanisole/triisopropylsilane:3,6-dioxa-1,8-octanedithiol(v/v/v/v/v/v), and the crude peptide was recovered by precipitation withdiethyl ether. The crude peptide was purified by reverse-phasehigh-performance liquid chromatography, and its purity and identity wereconfirmed by analytical reverse-phase high-performance liquidchromatography and matrix-assisted laser-desorption mass-spectrometry(m/z=2137.1 ((M+H)+)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Representative compounds were serially diluted in dimethyl sulfoxide(DMSO) starting at 50 μM (2× starting concentration; 10% DMSO) and 10 μLwere transferred into a 384-well plate. Then 10 μL of aprotein/probe/antibody mix was added to each well at finalconcentrations listed in TABLE 1. The samples are then mixed on a shakerfor 1 minute and incubated for an additional 3 hours at roomtemperature. For each assay, the probe/antibody andprotein/probe/antibody were included on each assay plate as negative andpositive controls, respectively. Fluorescence was measured on theENVISION plate reader (Perkin Elmer) using a 340/35 nm excitation filterand 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidineantibody) emission filters Inhibition constants (Ki) are shown in TABLE2 below and were determined using Wang's equation (Wang Z.-X. An ExactMathematical Expression For Describing Competitive Binding Of TwoDifferent Ligands To A Protein Molecule. FEBS Lett. 1995, 360:111-4).

TABLE 1 Protein, Probe And Antibody Used For TR-FRET Assays Anti-Protein Probe Anti- body Protein Probe (nM) (nM) body (nM) GST-F-Bak Peptide 1 100 Tb- 1 Bcl-2 Probe Acetyl- anti- GQVGRQLAIIGDK GST(6-FAM) INR-amide (SEQ ID NO: 1) 6-FAM = 6-carboxyfluorescein.; Tb =terbium; GST = glutathione S-transferase

TABLE 2 TR-FRET Bcl-2 Binding Ki (μM) TR-FRET Example Binding: Bcl-2 No.Ki (μM) 1 0.051449 2 0.082918 3 0.051702 5 0.176183 6 0.703735 70.000084 8 0.000064 9 0.000307 10 0.743178 11 0.177064 12 0.392534 130.387693 14 0.408575 15 0.282112 16 0.037859 17 0.356257 18 0.128531 190.234118 20 0.048076 22 0.188226 23 0.447133 24 0.3421 25 0.372106 260.393356 27 0.433996 28 0.417285 29 0.339986 30 0.269175 31 0.138755 320.43792 33 0.000649 34 0.001791 35 0.002067 36 0.293805 39 0.020238 400.000407 41 0.000053 42 0.000039 43 0.046497 44 0.024776 45 0.0067348 460.0017502 47 0.020416 48 0.001637

The inhibition constant (K_(i)) is the dissociation constant of anenzyme-inhibitor complex or a protein/small molecule complex, whereinthe small molecule is inhibiting binding of one protein to anotherprotein. So a large K_(i) value indicates a low binding affinity and asmall K_(i) value indicates a high binding affinity.

The data in TABLE 2 shows inhibition constants for the inhibition of aBak BH3 peptide probe to Bcl-2 protein and indicate that compoundsaccording to the invention have high binding affinities foranti-apoptotic Bcl-2 protein. The compounds are therefore expected tohave utility in treatment of diseases during which anti-apoptotic Bcl-2protein is expressed.

It is expected that, because compounds having Formula I bind to Bcl-2,they would also have utility as binders to anti-apoptotic proteinshaving close structural homology to Bcl-2, such as, for example,anti-apoptotic Bcl-X_(L), Bcl-w, Mcl-1 and Bfl-1/A1 proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer spleen cancer, and the like is described in commonly-owned PCT US2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.

Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.

Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula (I) would inhibitgrowth of cells expressing Bcl-2 proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis. Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficiency (common variablehypogammaglobulinaemia), conjunctivitis, connective tissue diseaseassociated interstitial lung disease, contact dermatitis, Coombspositive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease,cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis,culture negative sepsis, cystic fibrosis, cytokine therapy associateddisorders, Crohn's disease, dementia pugilistica, demyelinatingdiseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma,dermatologic conditions, dermatomyositis/polymyositis associated lungdisease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus,Diffuse Lewy body disease, dilated cardiomyopathy, dilated congestivecardiomyopathy, discoid lupus erythematosus, disorders of the basalganglia, disseminated intravascular coagulation, Down's Syndrome inmiddle age, drug-induced interstitial lung disease, drug-inducedhepatitis, drug-induced movement disorders induced by drugs which blockCNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis,endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis,Epstein-Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, female infertility, fibrosis, fibroticlung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cellarteritis, glomerular nephritis, glomerulonephritides, Goodpasture'ssyndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease),gouty arthritis, graft rejection of any organ or tissue, graft versushost disease, gram negative sepsis, gram positive sepsis, granulomas dueto intracellular organisms, group B streptococci (GBS) infection,Grave's disease, haemosiderosis associated lung disease, hairy cellleukemia, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto'sthyroiditis, hay fever, heart transplant rejection, hemachromatosis,hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia,hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura,hemorrhage, Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B.Hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease,hypoparathyroidism, Huntington's chorea, hyperkinetic movementdisorders, hypersensitivity reactions, hypersensitivity pneumonitis,hyperthyroidism, hypokinetic movement disorders,hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison'sdisease, idiopathic leucopaenia, idiopathic pulmonary fibrosis,idiopathic thrombocytopaenia, idiosyncratic liver disease, infantilespinal muscular atrophy, infectious diseases, inflammation of the aorta,inflammatory bowel disease, insulin dependent diabetes mellitus,interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis,ischemia-reperfusion injury, ischemic stroke, juvenile perniciousanaemia, juvenile rheumatoid arthritis, juvenile spinal muscularatrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplantrejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myclodyplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaccus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis. Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjörgren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthropathy,spondyloarthopathy, sporadic, polyglandular deficiency type I sporadic,polyglandular deficiency type II, Still's disease, streptococcalmyositis, stroke, structural lesions of the cerebellum, Subacutesclerosing panencephalitis, sympathetic ophthalmia, Syncope, syphilis ofthe cardiovascular system, systemic anaphylaxis, systemic inflammatoryresponse syndrome, systemic onset juvenile rheumatoid arthritis,systemic lupus erythematosus, systemic lupus erythematosus-associatedlung disease, systemic sclerosis, systemic sclerosis-associatedinterstitial lung disease, T-cell or FAB ALL, Takayasu'sdisease/arteritis, Telangiectasia, Th2 Type and Th1 Type mediateddiseases, thromboangitis obliterans, thrombocytopenia, thyroiditis,toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2autoimmune hepatitis (anti-LKM antibody hepatitis), type B insulinresistance with acanthosis nigricans, type III hypersensitivityreactions, type IV hypersensitivity, ulcerative colitic arthropathy,ulcerative colitis, unstable angina, uremia, urosepsis, urticaria,uveitis, valvular heart diseases, varicose veins, vasculitis, vasculiticdiffuse lung disease, venous diseases, venous thrombosis, ventricularfibrillation, vitiligo acute liver disease, viral and fungal infections,vital encephalitis/aseptic meningitis, vital-associated hemaphagocyticsyndrome, Wegener's granulomatosis, Wernicke-Korsakoff syndrome.Wilson's disease, xenograft rejection of any organ or tissue, yersiniaand salmonella-associated arthropathy and the like.

SCHEMES AND EXPERIMENTALS

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC.HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriaztol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Compounds of Formula (4) can be prepared as shown in SCHEME 1, and canbe used as described in SCHEME 8 to prepare compounds of Formula I,which are representative of the compounds of the present invention.Compounds of Formula (I) wherein R is alkyl, can be converted tocompounds of Formula (2) using Z³L¹MgX¹, wherein X¹ is a halide, in asolvent such as but not limited to ether or tetrahydrofuran. Compoundsof Formula (3) can be prepared from compounds of Formula (2) using astrong base such as NaH and R⁵⁷X², wherein X² is a halide and R⁵⁷ is asdescribed herein. Compounds of Formula (3), when treated with aqueousNaOH or LiOH, will provide compounds of Formula (4).

As shown in SCHEME 2, compounds of Formula (5) can be reacted withcompounds of Formula (6) and a reducing agent to provide compounds ofFormula (7). Examples of reducing agents include sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, polymer supportedcyanoborohydride, and the like. The reaction is typically performed in asolvent such as but not limited to methanol, tetrahydrofuran, anddichloromethane or mixtures thereof. Compounds of Formula (8) can beprepared from compounds of Formula (7) as described in SCHEME 1, and canbe used as described in SCHEME 8 to prepare compounds of Formula I.

Compounds of Formula (9), when reacted with a compound a Formula (10)wherein X is a halide or triflate, and a base will provide a compound ofFormula (11). Bases useful in the reaction include triethylamine,diisopropylethylamine and the like. Compounds of Formula (13), wherein Yis as described herein for substituents on Z³, can be prepared fromcompounds of Formula (11) and compounds of Formula (12) using Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature. Compounds of Formula (14) can be preparedfrom compounds of Formula (13) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula I.

As shown in SCHEME 4, compounds of Formula (17) can be prepared fromcompounds of Formula (15) and compounds of Formula (16), wherein R isalkyl and R³⁸ is as described herein, using Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as LiAlH₄ in a solvent such asbut not limited to diethyl ether or THF. Compounds of Formula (19) canbe prepared from compounds of Formula (18) using Dess-Martin periodinaneor Swern oxidation conditions known to those skilled in the art andreadily available in the literature. Compounds of Formula (19) can bereacted with a compound of Formula (5) and a reducing agent to providecompounds of Formula (20). Examples of reducing agents include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,polymer supported cyanoborohydride, and the like. The reaction istypically performed in a solvent such as but not limited to methanol,tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixturesthereof. Compounds of Formula (21) can be prepared from compounds ofFormula (20) as described in SCHEME 1, and can be used as described inSCHEME 8 to prepare compounds of Formula I.

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, maybe converted to compounds of Formula (23) by reacting the former,wherein X¹ is Cl, Br, I, or CF₃SO₃—, and compounds of Formula R⁴¹—OH anda catalyst, with or without a first base. Examples of catalysts includecopper(I) trifluoromethanesulfonate toluene complex, PdCl₂, Pd(OAc)₂,and Pd₂(dba)₃. Examples of first bases include triethylamine,N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, and mixtures thereof.

Compounds of Formula (22) may also be converted to compounds of Formula(23) by reacting the former, when X¹ is Cl, F, or NO₂, and compounds ofFormula R⁴¹—OH with a first base. Examples of first bases includetriethylamine, N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, andmixtures thereof.

Compounds of Formula (18) can be reacted with mesyl chloride and a basesuch as but not limited to triethylamine, followed byN-t-butoxycarbonylpiperazine, to provide compounds of Formula (24).Compounds of Formula (25) can be prepared by reacting compounds ofFormula (24) with triethylsilane and trifluoroacetic acid. Compounds ofFormula (25) can be reacted with compounds of Formula (26) and HK₂PO₄ toprovide compounds of Formula (27) in a solvent such as but not limitedto dimethylsulfoxide. Compounds of Formula (28) can be prepared fromcompounds of Formula (27) as described in SCHEME 1, and can be used asdescribed in SCHEME 8 to prepare compounds of Formula I.

As shown in SCHEME 7, compounds of Formula (I) can be reacted with anappropriate triphenylphosphonium bromide of Formula (29) and a base suchas but not limited to sodium hydride or n-butyllithium to providecompounds of Formula (30). The reaction is typically performed in asolvent such as THF or DMSO. Compounds of Formula (31) can be preparedfrom compounds of Formula (30) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula I.

As shown in SCHEME 8, compounds of Formula (32), which can be preparedas described herein, may be converted to compounds of Formula (33) byreacting the former with ammonia. Compounds of Formula (33) may beconvened to compounds of Formula (I) by reacting the former andcompounds of Formula (4), (8), (14), (21), (28), (31), or (37) and acoupling agent, with or without a first base. Examples of couplingagents include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride, 1,1′-carbonyldiimidazole, andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.Examples of first bases include triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

Compounds of Formula (33), prepared as described in SCHEME 1, may alsobe converted to compounds of Formula (I) by reacting the former andcompounds of Formula (34) and a first base. Examples of first basesinclude but are not limited to sodium hydride, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

As shown in SCHEME 10, compounds of Formula (35), wherein L is a bond,alkyl, O, S, S(O), S(O)₂, NH, etc., can be reacted with compounds ofFormula (36), to provide compounds of Formula (37). The reaction istypically performed at elevated temperatures in a solvent such as butnot limited to dimethylsulfoxide, and may require the use of a base suchas but not limited to potassium phosphate, potassium carbonate, and thelike. Compounds of Formula (38) can be prepared from compounds ofFormula (37) as described in SCHEME 1, and can be used as described inSCHEME 8 to prepare compounds of Formula I.

Compounds of Formula (39), wherein Y is as described herein forsubstituents on Z³, can be prepared from compounds of Formula (39A)wherein X is a halide or triflate, and Y—B(OH)₂ using Suzuki couplingconditions known to those skilled in the art and readily available inthe literature. Compounds of Formula (39) can be reacted with tert-butylpiperazine-1-carboxylate and a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of Formula (40). The reactionis typically performed in a solvent such as but not limited to methylenechloride. Compounds of Formula (41) can be prepared from compounds ofFormula (40) by reacting the latter with R⁵⁷X, wherein X is a halide,and NaH in a solvent such as N,N-dimethylformamide, and then theresulting material can be treated with triethylsilane andtrifluoroacetic acid in dichloromethane. Compounds of Formula (41) canbe used as described in Scheme 10 wherein L¹-Z³ is as shown in Formula(41).

As shown in SCHEME 12, substituted piperazin-2-ones wherein R⁵⁷ isalkyl, can be reacted with compounds of Formula (6) and a reducing agentsuch as sodium triacetoxyborohydride in dichloromethane to providecompounds of Formula (42). Compounds of Formula (42) can be reduced tocompounds of Formula (43) using a reducing agent such as but not limitedto lithium aluminum hydride in a solvent such as but not limited totetrahydrofuran. Compounds of Formula (43) can be used as described inScheme 10 wherein L¹-Z³ is as shown in Formula (43).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5(CambridgeSoft, Cambridge, Mass.). Intermediates were named usingChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

EXAMPLE 14-[4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamideEXAMPLE 1A (R)-benzyl4-(dimethylamino)-1-hydroxy-4-oxobutan-2-ylcarbamate

A solution of 3-(S)-((carbobenzyloxy)amino)-γ-butyrolactone (preparedaccording to the procedure described in McGarvey, G. J.; Williams, J.M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am. Chem. Soc. 1986, 108,4943-4952, 7.72 g) in THF (100 mL) was saturated with gaseousdimethylamine, stirred at room temperature for 16 hours, andconcentrated. The residue was filtered through a plug of silica geleluting with 50% acetone in hexanes to give the desired product.

EXAMPLE 1B (R)-benzyl4-(dimethylamino)-4-oxo-1-(phenylthio)butan-2-ylcarbamate

A solution of EXAMPLE 1A (8.45 g) in toluene (15 mL) was treated withtributylphosphine (9.76 mL), and diphenyldisulfide (7.30 g) and washeated to 80° C. for 16 hours. The reaction mixture was concentrated andpurified by column chromatography on silica gel eluting with a gradientof 0-50% ethyl acetate in hexanes to give the desired product.

EXAMPLE 1C (R)-3-amino-N,N-dimethyl-4-(phenylthio)butanamide

A suspension of EXAMPLE 1B (10.60 g) in 50 mL 30% HBr/acetic acid wasstirred at room temperature overnight. The resulting homogeneousreaction mixture was concentrated, diluted with water (200 mL) and 5%HCl (100 mL), and washed with diethyl ether (3×). The aqueous phase wasadjusted to pH ˜8-9 with solid Na₂CO₃ and extracted with dichloromethane(5×). The combined organic phases were dried (MgSO₄), filtered, andconcentrated to give the desired product.

EXAMPLE 1D (R)—N¹,N¹-dimethyl-4-(phenylthio)butane-1,3-diamine

A solution of EXAMPLE 1C (8.68 g) in THF (200 mL) was treated withBH₃-dimethylsulfide (18.2 mL) at room temperature, stirred overnight,treated slowly with methanol (20 mL), followed by 2N HCl (50 mL),stirred overnight, and concentrated. The resulting residue was purifiedby silica gel chromatography eluting with 5% 7N NH₃/CH₃OH indichloromethane to give the desired product.

EXAMPLE 1E(R)-5-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-4-nitrothiophene-2-sulfonamide

2-Chloro-3-nitrothiophene-5-sulfonamide (2.18 g), EXAMPLE 1D (1.14 g),and triethylamine (1 g) were stirred in dioxane (30 mL) at 90° C. for 24hours. The solution was diluted with ethyl acetate, washed with NaH₂PO₄solution and brine, dried over Na₂SO₄, filtered and concentrated. Theproduct was triturated from ethyl acetate.

EXAMPLE 1F ethyl4-(4-(cyclohexylmethyl)-4-hydroxypiperidin-1-yl)benzoate

A solution of cyclohexylmethylmagnesium bromide (1.90 mL of a 2Msolution in THF) at −78° C. was treated with ethyl4-(4-oxo-1-piperidinyl)benzoate (prepared according to the proceduredescribed in Synthesis 1981, 606-608, 0.30 g), and was allowed to warmto room temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and saturated aqueous NH₄Cl and the aqueous layerwas extracted with ethyl acetate (2×). The combined organic layers weredried (MgSO₄), filtered, and concentrated. The resulting residue waspurified by silica gel chromatography eluting with 20% ethyl acetate togive the product.

EXAMPLE 1G ethyl4-(4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl)benzoate

A solution of EXAMPLE 1F (380 mg) in THF (5 mL) was treated with NaH (96mg, 60% dispersion in mineral oil), heated to 50° C. for 2 hours, andtreated with hexamethylphosphoramide (1 mL) followed by MeI (1 mL). Thereaction mixture was refluxed overnight, cooled to 0° C., and dilutedwith saturated aqueous NaHSO₄ solution (10 mL). The resulting two-phasemixture was separated, the aqueous phase was extracted twice with ether,and the combined organic layers washed with water and brine. Afterdrying over MgSO₄, the mixture was concentrated in vacuo and purified bysilica gel chromatography eluting with 15% ethyl acetate in hexanes.

EXAMPLE 1H 4-(4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl)benzoic acid

A solution of EXAMPLE 1G (300 mg) in dioxane (5 mL) was treated with 1NNaOH (2 mL), stirred overnight, acidified with 1N HCl, extracted withethyl acetate (3×), dried (MgSO₄), and filtered. Concentration of thefiltrate gave the desired product.

EXAMPLE 1I4-[4-(cyclohexylmethyl)-4-methoxypiperidin-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide

EXAMPLE 1E (60 mg), EXAMPLE 1H (65 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (65 mg),and 4-dimethylaminopyridine (22 mg) were stirred in CH₂Cl₂ (4 mL) for 24hours. The reaction was cooled and chromatographed on silica gel with50-100% ethyl acetate in hexanes followed by 1/10/89triethylamine/methanol/ethyl acetate. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06(br s, 1H), 7.77 (d, 2H), 7.44 (s, 1H), 7.35 (d, 2H), 7.26 (dd, 2H),7.11 (t, 1H), 6.84 (d, 2H), 3.60 (m, 1H), 3.45 (m, 2H), 3.32 (m, 1H),3.07 (m, 4H), 2.97 (m, 2H), 2.77 (m, 1H), 2.66 (m, 1H), 2.43 (s, 6H),2.05 (m, 2H), 1.75 (m, 2H), 1.59 (m, 2H), 1.48 (m, 2H), 1.33 (m, 2H),1.17 (m, 6H), 0.94 (m, 2H).

EXAMPLE 2N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidin-1-yl]benzamideEXAMPLE 2A ethyl 4-(4-hydroxy-4-(3-methylbenzyl)piperidin-1-yl)benzoate

This EXAMPLE was prepared by substituting 3-methylbenzylmagnesiumchloride for cyclohexylmethylmagnesium bromide in EXAMPLE 1F

EXAMPLE 2B ethyl 4-(4-methoxy-4-(3-methylbenzyl)piperidin-1-yl)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 2A for EXAMPLE 1F inEXAMPLE 1G.

EXAMPLE 2C 4-(4-methoxy-4-(3-methylbenzyl)piperidin-1-yl)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 2B for EXAMPLE 1G inEXAMPLE 1H.

EXAMPLE 2DN-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidin-1-yl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 2C for EXAMPLE 1H inEXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (br s, 1H), 7.76 (d, 2H),7.44 (s, 1H), 7.35 (d, 2H), 7.26 (dd, 2H), 7.16 (m, 2H), 6.89 (m, 3H),6.82 (d, 2H), 4.05 (m, 1H), 3.61 (m, 1H), 3.48 (m, 2H), 3.32 (m, 2H),3.27 (s, 3H), 3.17 (s, 2H), 3.07 (m, 1H), 2.92 (m, 2H), 2.74 (s, 6H),2.27 (s, 3H), 2.07 (m, 2H), 1.67 (m, 2H), 1.52 (m, 2H).

EXAMPLE 3N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazin-1-yl]benzamideEXAMPLE 3A ethyl 4-(4-(3,3-diphenylallyl)piperazin-1-yl)benzoate

A suspension of ethyl 4-piperazin-1-ylbenzoate (1.36 g) and3,3-diphenylacrylaldehyde (1.56 g) in dichloromethane (10 mL) andmethanol (10 mL) was treated with polymer-supported cyanoborohydride(2.47 mmol/g, 6 g), shaken at room temperature for 24 hours, andfiltered. The resin was washed with 1:1 dichloromethane/methanol (10mL×3) and the combined filtrates were concentrated. The concentrate waspurified by silica gel chromatography eluting with a gradient from10%-50% ethyl acetate/hexanes to provide the desired product.

EXAMPLE 3B 4-(4-(3,3-diphenylallyl)piperazin-1-yl)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 3A for EXAMPLE 1G inEXAMPLE 1H.

EXAMPLE 3CN-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazin-1-yl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3B for EXAMPLE 1H inEXAMPLE 1I. ¹H NMR (500 MHz, DMSO-d₆) δ 10.25 (br s, 1H), 9.08 (br s,1H), 7.78 (d, 2H), 7.43 (m, 2H), 7.35 (m, 3H), 7.30 (d, 2H), 7.20-7.29(m, 5H), 7.16 (m, 3H), 6.84 (d, 2H), 6.22 (t, 1H), 3.59 (m, 1H), 3.45(m, 4H), 3.32 (m, 4H), 3.03 (m, 4H), 2.78 (m, 1H), 2.65 (m, 1H), 2.42(s, 6H), 2.07 (m, 2H).

EXAMPLE 44-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-([2-(phenylthio)ethyl]amino)piperidin-1-yl)sulfonyl]benzamide EXAMPLE 4A ethyl4-(piperazin-1-yl)benzoate

A suspension of piperazine (129.2 g, 1.5 mol), ethyl-4-fluorobenzoate(84 g, 0.5 mol), and potassium carbonate (103.65 g, 0.75 mol) in DMSO(200 mL) was stirred at 120° C. under N₂ for six hours. The reactionmixture was then cooled to room temperature, poured into water (800 mL),and stirred for 30 minutes. The desired product was collected byfiltration and carried to the next step without further purification.

EXAMPLE 4B ethyl 4-(4-(2-bromobenzyl)piperazin-1-yl)benzoate

A solution of EXAMPLE 4A (23.43 g, 100.0 mmol), 2-bromobenzyl bromide(26.24 g, 105.0 mmol) and diisopropylethylamine (20.94 mL, 120.0 mmol)in acetonitrile (200 mL) was stirred at room temperature for two hours.The resulting precipitate was collected by filtration to give thedesired product, which was used without further purification.

EXAMPLE 4C ethyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

A suspension of EXAMPLE 4B (13.83 g, 34.3 mmol), 4-chlorophenylboronicacid (7.04 g, 45.0 mmol), bis(triphenylphosphine)palladium(II)dichloride (0.481 g, 0.686 mmol, 2 mol %) and aqueous 2M Na₂CO₃ (22.5mL, 45.0 mmol) in dimethoxyethane/H₂O/ethanol (7:3:2, 200 mL) was heatedat 90° C. for 4.5 hours and diluted with ethyl acetate (200 mL). Thelayers were separated and the organic phase was dried (MgSO₄), filtered,and concentrated. The residue was purified by silica gel chromatographyeluting with a gradient from 5%-40% ethyl acetate/hexanes to give thedesired product.

EXAMPLE 4D 4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

A suspension of EXAMPLE 4C (13.0 g, 29.9 mmol) and LiOH monohydrate(3.78 g, 90.0 mmol) in dioxane (250 mL) and water (100 mL) was heated at95° C. for 16 hours, concentrated to dryness, treated with water (600mL), heated to 80° C., and filtered. The filtrate was treated with 1MHCl (90 mL) and the resulting precipitate was collected by filtrationand dried to give the desired product.

EXAMPLE 4E tert-butyl 4-oxopiperidin-1-ylsulfonylcarbamate

Chlorosulfonyl isocyante (1.044 g, 7.353 mmol) was added todichloromethane (20 mL) and the mixture was cooled to 0° C. Tert-butanol(544 mg, 7.353 mmol) in dichloromethane (3 mL) was added and, thesolution was stirred at 0° C. for 30 minutes. This solution was thenadded to a separate flask containing 4-piperidone hydrochloride (1.00 g,7.353 mmol) and triethylamine (3.1 mL, 22.059 mmol) in dichloromethane(20 mL), which had been cooled to 0° C. After addition, the solution wasallowed to warm to room temperature and stir for two hours. The mixturewas then partitioned between dichloromethane and saturated aqueousammonium chloride. The aqueous layer was extracted with dichloromethanethree times, and the combined organic extracts were dried over anhydrousmagnesium sulfate. The solution was concentrated and purified by flashcolumn chromatography on silica gel with 0% ethyl acetate indichloromethane increasing to 20% ethyl acetate in dichloromethane.

EXAMPLE 4F 4-oxopiperidine-1-sulfonamide

EXAMPLE 4E (500 mg) was dissolved in 1,4-dioxane (4 mL), treated with 4MHCl (4 mL), and stirred at room temperature for three hours. Thesolution was concentrated and purified by flash column chromatography onsilica gel with 0% acetonitrile (dichloromethane) increasing to 40%acetonitrile (dichloromethane).

EXAMPLE 4G4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-oxopiperidin-1-ylsulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4F for EXAMPLE 1E andEXAMPLE 4D for EXAMPLE 1H in EXAMPLE 1I.

EXAMPLE 4H4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide

EXAMPLE 4G (100 mg, 0.176 mmol), 2-(phenylthio)ethanamine (30 mg, 0.194mmol), sodium triacetoxyborohydride (56 mg, 0.264 mmol), and acetic acid(11 μL, 0.194 mmol) were added to 1,2-dichloroethane (2 mL) and mixed atroom temperature for six hours. The solvent was removed under vacuum,and the residue was treated with water. The precipitate was filtered,dried, dissolved in dimethylsulfoxide/methanol with a couple of drops oftriethylamine, and purified by preparative HPLC on a Phenomenex LunaC8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A,7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A). ¹H NMR (400MHz, DMSO-d₆) δ 11.53 (bs, 1H), 8.92 (bs, 2H), 7.76 (d, 2H), 7.70 (bs,1H), 7.48 (m, 4H), 7.38-7.26 (m, 7H), 7.24-7.17 (m, 1H), 4.18 (bs, 2H),3.74 (d, 4H), 3.21-3.16 (m, 6H), 3.08 (bs, 4H), 2.87 (t, 4H), 2.04 (d,2H), 1.48 (m, 2H).

EXAMPLE 5N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

EXAMPLE 4H (30 mg, 0.0426 mmol), acetic anhydride (4.3 mg, 0.0426 mmol),and triethylamine (18 μL, 0.128 mmol) were added to dichloromethane (1mL) and stirred at room temperature for two hours. The solvent wasremoved under vacuum, dissolved in dimethylsulfoxide/methanol, andpurified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIAcolumn (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min(0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95%A, 10.0-12.0 min linear gradient 95-10% A). ¹H NMR (400 MHz, DMSO-d₆) δ11.50 (bs, 1H), 7.82 (d, 2H), 7.74 (bs, 1H), 7.52 (d, 4H), 7.40 (t, 4H),7.35-7.25 (m, 3H), 7.18 (dt, 1H), 6.94 (d, 2H), 4.26 (bs, 2H), 3.96 (t,1H), 3.75 (d, 4H), 3.28 (dt, 4H), 3.10-2.85 (m, 8H), 2.04 (s, 2H), 1.88(s, 1H), 1.75-1.56 (m, 4H).

EXAMPLE 64-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidin-1-yl)sulfonyl]benzamide

EXAMPLE 4H (30 mg, 0.0426 mmol), formaldehyde (37% solution in water, 10μL, 0.128 mmol), and sodium triacetoxyborohydride (14 mg, 0.0639 mmol)were added to acetonitrile (0.8 mL) and water (0.2 mL). The solvent wasremoved under vacuum, dissolved in dimethylsulfoxide/methanol, andpurified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIAcolumn (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min(0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95%A, 10.0-12.0 min linear gradient 95-10% A).

¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (bs, 1H), 9.84 (bs, 1H), 7.54 (d, 2H),7.49 (bs, 1H), 7.26 (d, 4H), 7.12 (d, 4H), 7.11-7.07 (m, 3H), 6.99 (t,1H), 6.69 (d, 2H), 3.98 (bs, 2H), 3.56 (d, 2H), 3.33-3.11 (m, 4H),3.09-2.91 (m, 7H), 2.68 (t, 4H), 2.49 (s, 3H), 1.72 (d, 2H), 1.38 (bs,2H).

EXAMPLE 74-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamideEXAMPLE 7A (R)-benzyl 4-oxo-1-(phenylthio)butan-2-ylcarbamate

To a 100 mL three necked round-bottom flask charged with EXAMPLE 1B(3.75 g, 10.0 mmol) and bis(cyclopentadienyl)zirconium chloride hydride(3.85 g, 15.0 mmol) was added 50 mL of anhydrous THF through a syringeunder argon (the air in the system was replaced by vacuum-argonreplacement three times). The mixture was stirred at room temperaturefor 20 minutes, and it became a clear solution during the stirring. TLCshowed the reaction was complete and the mixture was concentrated. Theresidue was loaded on a silica gel pad and flushed with hexane/ethylacetate (1:1, 300 mL). Concentration gave title compound.

EXAMPLE 7B (R)-benzyl4-(isopropyl(methyl)amino)-1-(phenylthio)butan-2-ylcarbamate

To a 250 mL round-bottom flask containing EXAMPLE 7A (2.87 g, 8.71 mmol)was added 50 mL of 1,2-dichloroethane and methylisopropylamine (1.92 g,26.25 mmol) and sodium triacetoxyborohydride (3.0 g, 14.1 mmol). Themixture was stirred at room temperature under N₂ for two hours. Themixture was diluted with ethyl acetate (200 mL) and washed with 2N NaOH,water, brine and dried over Na₂SO₄. The solvent was removed under vacuumto give title compound.

EXAMPLE 7C (R)—N′-isopropyl-N′-methyl-4-(phenylthio)butane-1,3-diamine

EXAMPLE 7B (0.56 g, 1.47 mmol) was dissolved in acetonitrile (10 mL) andtrimethylsilyl iodide (400 μL) was added. The mixture was stirred atroom temperature overnight. The mixture was quenched with methanol,concentrated under vacuum, and the residue was dissolved in ethylacetate (200 mL) and washed with 1.5% HCl (50 mL) twice. The combinedaqueous layers were basified with solid NaOH and extracted with ethylacetate (100 mL×3). The combined extracts were washed with brine anddried over Na₂SO₄. Evaporation of solvent gave title compound.

EXAMPLE 7D(R)-5-(4-(isopropyl(methyl)amino)-1-(phenylthio)butan-2-ylamino)-4-nitrothiophene-2-sulfonamide

To a 20 mL vial containing EXAMPLE 7C (0.43 g, 1.69 mmol) was added2-chloro-3-nitrothiophene-5-sulfonamide (0.409 g, 1.69 mmol) and DMSO (5mL) followed by diisopropylethylamine (1 mL, 5.74 mmol). The mixture wasstirred at 60 OC overnight, and The mixture was diluted with ethylacetate (150 mL) and washed with aqueous NaHCO₃, water and brine. Afterdrying over Na₂SO₄ and evaporation of solvent, the residue was loaded ona silica gel column and eluted with ethyl acetate/dichloromethane(saturated with NH₃) to give title compound.

EXAMPLE 7E4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide

The title compound was prepared as in EXAMPLE 1I, replacing EXAMPLE 1Eand EXAMPLE 1H with EXAMPLE 7D and EXAMPLE 4D, respectively. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.98 (m, 1H), 7.83 (m, 2H), 7.70 (m, 1H), 7.52 (m,4H), 7.35 (m, 6H), 7.16 (m, 4H), 6.96 (m, 2H), 3.77 (m, 2H), 3.59 (m,5H), 3.21 (m, 7H), 2.64 (t, 3H), 2.52 (d, 6H), 1.19 (d, 4H).

EXAMPLE 84-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamideEXAMPLE 8A ethyl 2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a cooled (0° C.) stirring suspension of NaH (0.983 g 60% in mineraloil, washed with hexane three times) in ether (50 ml) was added ethyl2-oxocyclohexanecarboxylate (3.2 g, 20.5 mmol). The mixture was stirredat 0° C. for 30 minutes before the addition of trifluoromethanesulfonicanhydride (4.2 mL, 25 mmol). The mixture was then stirred at roomtemperature overnight. The mixture was diluted with ether (200 mL) andwashed with 5% HCl, water and brine. After drying over Na₂SO₄,evaporation of solvent gave crude product which was used without furtherpurification.

EXAMPLE 8B ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate

To a solution of EXAMPLE 8A (2.88 g, 10 mmol), 4-chlorophenylboronicacid (1.88 g, 12 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.578 g, 0.5 mmol) in toluene (40 ml) and ethanol (10 ml) was added 2NNa₂CO₃ (10 mL). The mixture was stirred at reflux overnight. The mixturewas diluted ether (300 mL) and washed with water, brine and dried overNa₂SO₄. After evaporation of solvent, the residue was loaded on a columnand eluted with 3% ethyl acetate in hexane to give title compound.

EXAMPLE 8C (2-(4-chlorophenyl)cyclohex-1-enyl)methanol

To a solution of EXAMPLE 8B (1.6 g, 6.38 mmol) in ether (20 mL) wasadded LiAlH₄ (1.2 g, 32 mmol). The mixture was stirred at roomtemperature for four hours. The mixture was acidified carefully with 5%HCl and extracted with ethyl acetate (100 mL×3) and washed with water,brine and dried over Na₂SO₄. After evaporation, the crude product wasloaded on a column and eluted with 10% ethyl acetate in hexane to givetitle compound.

EXAMPLE 8D 2-(4-chlorophenyl)cyclohex-1-enecarbaldehyde

To a solution of oxalyl chloride (1.1 g, 8.63 mmol) in dichloromethane(30 ml) at −78° C. was added dimethylsulfoxide (6.12 mL, 86 mmol). Themixture was stirred at −78° C. for 30 minutes, and then a solution ofEXAMPLE 8C (1.2 g, 5.75 mmol) in dichloromethane (10 mL) was added. Themixture was stirred at −78° C. for two hours before the addition oftriethylamine (10 mL). The mixture was stirred overnight and thetemperature was allowed to rise to room temperature. The mixture wasdiluted with ether (300 mL) and washed with water, brine and dried overNa₂SO₄. Evaporation of solvent and column purification (5% ethyl acetatein hexane) gave title compound.

EXAMPLE 8E ethyl4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 8D (100 mg, 0.484 mmol) and EXAMPLE 4A (177 mg,0.484 mmol) in 1,2-dichloroethane (10 mL) was added sodiumtriacetoxyborohydride (154 mg, 0.726 mmol). The mixture was stirred atroom temperature overnight. The mixture was diluted with ethyl acetate(200 mL) and washed with 2% NaOH, water and brine. After drying overNa₂SO₄, the solvent was concentrated under vacuum, and the residue wasloaded on a column and eluted with 30% ethyl acetate in hexane to givetitle compound.

EXAMPLE 8F4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 8E (254 mg, 0.457 mmol) in tetrahydrofuran (4mL), methanol (2 mL) and water (2 mL) was added lithium hydroxidemonohydrate (126 mg, 3 mmol). The mixture was stirred at roomtemperature overnight. The mixture was then neutralized with 5% HCl anddiluted with ethyl acetate (200 mL). After washing with brine, it wasdried over Na₂SO₄. Evaporation of solvent gave title compound.

EXAMPLE 8G4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide

The title compound was prepared as in EXAMPLE 1I, replacing EXAMPLE 1Eand EXAMPLE 1H with EXAMPLE 7D and EXAMPLE 8F respectively. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.97 (m, 1H), 7.83 (m, 2H), 7.68 (m, 1H), 7.42 (m,2H), 7.30 (m, 2H), 7.17 (m, 5H), 6.97 (m, 2H), 3.91 (m, 2H), 3.66 (m,3H), 3.18 (m, 7H), 2.87 (m, 3H), 2.64 (t, 3H), 2.51 (d, 6H), 2.24 (m,4H), 1.72 (m, 3H), 1.18 (m, 6H).

EXAMPLE 94-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamideEXAMPLE 9A methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate

To a suspension of hexane-washed NaH (0.72 g, 60%, 18 mmol) intetrahydrofuran (30 mL) was added a solution of4,4-dimethylcyclohexanone (2.0 g, 15.6 mmol) in tetrahydrofuran (20 mL).The suspension was stirred at room temperature for 30 minutes. Thendimethylcarbonate (6.31 mL, 75 mmol) was added dropwise by syringe. Themixture was heated to reflux for four hours. The mixture was acidifiedwith 5% HCl and extracted with dichloromethane (100 mL×3) and washedwith water, brine, and dried over Na₂SO₄. After concentration, the crudeproduct was loaded on a column and eluted with 10% ethyl acetate inhexane to give title compound.

EXAMPLE 9B methyl5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

The title compound was prepared as in EXAMPLE 8A by substituting ethyl2-oxocyclohexanecarboxylate with EXAMPLE 9A.

EXAMPLE 9C methyl2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate

The title compound was prepared as in EXAMPLE 8B by substituting EXAMPLE8A with EXAMPLE 9B.

EXAMPLE 9D (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol

The title compound was prepared as in EXAMPLE 8C by substituting EXAMPLE8B with EXAMPLE 9C.

EXAMPLE 9E 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde

The title compound was prepared as in EXAMPLE 8D by substituting EXAMPLE8C with EXAMPLE 9D.

EXAMPLE 9F ethyl4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as in EXAMPLE 8E by substituting EXAMPLE8D with EXAMPLE 9E.

EXAMPLE 9G4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as in EXAMPLE 8F by substituting EXAMPLE8E with EXAMPLE 9F.

EXAMPLE 9H4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}benzamide

The title compound was prepared as in EXAMPLE 1I, replacing EXAMPLE 1Eand EXAMPLE 1H with EXAMPLE 7D and EXAMPLE 9G, respectively. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.96 (m, 1H), 7.83 (m, 2H), 7.67 (m, 1H), 7.42 (m,2H), 7.29 (m, 2H), 7.17 (m, 6H), 6.97 (m, 2H), 3.90 (m, 2H), 3.61 (m,8H), 3.19 (m, 3H), 2.65 (m, 3H), 2.23 (m, 5H), 2.04 (m, 2H), 1.48 (m,2H), 1.19 (m, 6H), 1.00 (s, 6H).

EXAMPLE 10N-{[(5Z)-5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H and(Z)—N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide forEXAMPLE 1E in EXAMPLE 1I. ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (d, 2H), 7.48(m, 5H), 7.38 (m, 2H), 7.24 (m, 1H), 6.83 (d, 2H), 3.84 (s, 2H), 3.17(m, 4H), 2.40 (m, 4H), 1.82 (s, 6H).

EXAMPLE 11N-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamideEXAMPLE 11A N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide

2-Acetamido-4-methylthiazole-5-sulfonyl chloride (0.50 g, 1.96 mmol) wasdissolved in THF (7 mL), cooled to 0° C., and concentrated NH₄OH (0.7mL) was added. After 3 hours the reaction was concentrated, diluted withwater, and extracted with CHCl₃/methanol. The organic layer was driedover Na₂SO₄. Filtration and concentration gave the product that was usedEXAMPLE 11B.

EXAMPLE 11BN-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl)}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 11A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done by preparative HPLC using a C18 column, 250×50 mm, 10μ, andeluting with a gradient of 20-100% CH₃CN vs. 0.1% TFA in water, givingthe product as a trifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d₆) δ12.60 (s, 1H), 12.30 (v br s, 1H), 9.60 (v br s, 1H), 7.80 (d, 2H), 7.75(br s, 1H), 7.52 (m, 4H), 7.40 (d, 2H), 7.36 (m, 1H), 6.94 (d, 2H), 4.38(br s, 1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H), 2.52 (s, 3H),2.18 (s, 3H).

EXAMPLE 12N-({5-[(benzoylamino)methyl]thien-2-yl}sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamideEXAMPLE 12A N-((5-sulfamoylthiophen-2-yl)methyl)benzamide

This EXAMPLE was prepared by substituting5-(benzamidomethyl)thiophene-2-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 12BN-({5-[(benzoylamino)methyl]thien-2-yl}sulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 12A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) 12.20 (ν br s,1H), 9.60 (ν br s, 1H), 9.26 (t, 1H), 7.87 (d, 2H), 7.79 (m, 3H), 7.67(d, 1H), 7.51 (m, 7H), 7.40 (d, 2H), 7.36 (m, 1H), 7.09 (d, 1H), 6.90(d, 2H), 4.64 (d, 2H), 4.38 (br s, 1H), 3.85 (br s, 1H), 3.40-2.80(envelope, 8H).

EXAMPLE 134-(4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H and6-chloroimidazo[2,1-b]thiazole-5-sulfonamide for EXAMPLE 1E in EXAMPLE1I, except here the purification was done as in EXAMPLE 11B. ¹H NMR (300MHz. DMSO-d₆) δ 9.60 (v br s, 1H), 8.04 (d, 1H), 7.79 (m, 3H), 7.63 (d,1H), 7.51 (m, 4H), 7.40 (d, 2H), 7.36 (m, 1H), 6.92 (d, 2H), 4.38 (br s,1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H).

EXAMPLE 144-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(morpholin-4-ylsulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andmorpholine-4-sulfonamide for EXAMPLE 1E in EXAMPLE 1I, except here thepurification was done as in EXAMPLE 11B. ¹H NMR (300 MHz. DMSO-d₆) δ11.58 (br s, 1H), 9.60 (v br s, 1H), 7.82 (d, 2H), 7.75 (br s, 1H), 7.55(m, 4H), 7.40 (d, 2H), 7.36 (m, 1H), 6.96 (d, 2H), 4.38 (br s, 1H), 3.85(br s, 1H), 3.61 (m, 4H), 3.40-2.80 (envelope, 8H), 3.25 (m, 4H).

EXAMPLE 154-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H and2,4-dimethylthiazole-5-sulfonamide for EXAMPLE 1E in EXAMPLE 1I, excepthere the purification was done as in EXAMPLE 11B. ¹H NMR (300 MHz,DMSO-d₆) δ 12.40 (v br s, 1H), 9.60 (v br s, 1H), 7.80 (d, 2H), 7.75 (brs, 1H), 7.55 (m, 4H), 7.40 (d, 2H), 7.36 (m, 1H), 6.94 (d, 2H), 4.38 (brs, 1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H), 2.65 (s, 3H), 2.55(s, 3H).

EXAMPLE 164-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)thien-3-yl]sulfonyl}benzamideEXAMPLE 16A 4-phenyl-5-(trifluoromethyl)thiophene-3-sulfonamide

This EXAMPLE was prepared by substituting4-phenyl-5-(trifluoromethyl)thiophene-3-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 16B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)thien-3-yl]sulfonyl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 16A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (v br s,1H), 9.60 (v br s, 1H), 8.80 (s, 1H), 7.77 (br s, 1H), 7.60 (d, 2H),7.53 (m, 4H), 7.40 (m, 3H), 7.35 (m, 3H), 7.16 (d, 2H), 6.89 (d, 2H),4.38 (br s, 1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H).

EXAMPLE 174-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-fluoro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamideEXAMPLE 17A 5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide

This EXAMPLE was prepared by substituting5-fluoro-3-methylbenzo[b]thiophene-2-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 17B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-fluoro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 17A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) δ 12.60 (v br s,1H), 9.60 (v br s, 1H), 8.12 (dd, 1H), 7.85 (d, 1H) 7.80 (m, 3H), 7.52(m, 4H), 7.46 (dd, 1H), 7.40 (d, 2H), 7.36 (m, 1H), 6.92 (d, 2H), 4.38(br s, 1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H), 2.66 (s, 3H).

EXAMPLE 18N-(1,3-benzothiazol-2-ylsulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamideEXAMPLE 18A benzo[d]thiazole-2-sulfonamide

Benzo[d]thiazole-2-sulfonamide was prepared as described by Roblin. Jr,R. O.; Clapp, J. W., J. Am. Chem. Soc. 1950, 72, 4890-4892.

EXAMPLE 18BN-(1,3-benzothiazol-2-ylsulfonyl)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 18A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (500 MHz, DMSO-d₆) δ 11.79 (br s,1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.78 (d, 2H), 7.74 (br s, 1H), 7.55 (m,6H), 7.40 (d, 2H), 7.34 (d, 1H), 6.87 (d, 2H), 4.36 (m, 2H), 3.80 (m,2H), 3.42 (m, 2H), 3.05 (m, 2H), 2.90 (m, 2H).

EXAMPLE 194-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-(thien-2-ylsulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andthiophene-2-sulfonamide for EXAMPLE 1E in EXAMPLE 1I, except here thepurification was done as in EXAMPLE 11B. ¹H NMR (500 MHz, DMSO-d₆) δ12.33 (br s, 1H), 8.02 (dd, 1H), 7.82 (dd, 1H), 7.78 (d, 2H), 7.75 (brs, 1H), 7.54 (m, 4H), 7.39 (d, 2H), 7.34 (m, 1H), 7.20 (dd, 1H), 6.94(d, 2H), 4.33 (m, 2H), 3.89 (m, 2H), 3.25 (m, 2H), 3.12 (m, 2H), 2.91(m, 2H).

EXAMPLE 204-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamideEXAMPLE 20A 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

This EXAMPLE was prepared by substituting5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 20B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 20A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (v br s,1H), 7.81 (d, 2H), 7.75 (br s, 1H), 7.55 (m, 4H), 7.40 (d, 2H), 7.39 (s,1H), 7.36 (m, 1H), 6.94 (d, 2H), 4.38 (br s, 1H), 3.85 (br s, 1H),3.40-2.80 (envelope, 8H), 2.78 (s, 3H), 2.62 (s, 3H).

EXAMPLE 21 ethyl4-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylateEXAMPLE 21A ethyl5-methyl-1,2-diphenyl-4-sulfamoyl-1H-pyrrole-3-carboxylate

This EXAMPLE was prepared by substituting methyl5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 21B ethyl4-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 21A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) δ 11.70 (br s,1H), 9.60 (v br s, 1H), 7.90 (d, 2H), 7.77 (br s, 1H), 7.53 (m, 4H),7.40 (m, 6H), 7.27 (m, 2H), 7.20 (m, 3H), 7.09 (m, 2H), 6.92 (d, 2H),4.38 (br s, 1H), 4.00 (q, 2H), 3.85 (br s, 1H), 3.40-2.80 (envelope,8H), 2.35 (s, 3H), 0.90 (t, 3H).

EXAMPLE 22 methyl5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylateEXAMPLE 22A methyl 1-methyl-5-sulfamoyl-1H-pyrrole-2-carboxylate

This EXAMPLE was prepared by substituting methyl5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 22B methyl5-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl)}-1-methyl-1H-pyrrole-2-carboxylate

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 22A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz. DMSO-d₆) δ 11.90 (br s,1H), 9.60 (v br s, 1H), 7.85 (d, 1H), 7.78 (m, 3H), 7.55 (m, 4H), 7.40(d, 2H), 7.36 (m, 1H), 7.15 (d, 1H), 7.92 (d, 2H), 4.38 (br s, 1H), 3.90(s, 3H), 3.85 (br s, 1H), 3.78 (s, 3H), 3.40-2.80 (envelope, 8H).

EXAMPLE 234-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazol-5-yl)isoxazol-4-yl]sulfonyl}benzamideEXAMPLE 23A 5-(1,3-dimethyl-H-pyrazol-5-yl)isoxazole-4-sulfonamide

This EXAMPLE was prepared by substituting5-(1,3-dimethyl-1H-pyrazol-4-yl)isoxazole-4-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 23B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazol-5-yl)isoxazol-4-yl]sulfonyl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 23A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz, DMSO-d₆) δ 11.90 (br s,1H), 9.60 (v br s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 7.78 (m, 3H), 7.55(m, 4H), 7.40 (d, 2H), 7.36 (m, 1H), 7.92 (d, 2H), 4.38 (br s, 1H), 3.85(br s, 1H), 3.83 (s, 3H), 3.40-2.80 (envelope, 8H), 2.37 (s, 3H).

EXAMPLE 244-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-chloro-3-methylisothiazol-5-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting4-chloro-3-methyl-isothiazole-5-sulfonamide for EXAMPLE 1E and EXAMPLE4D for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (300 MHz. DMSO-d₆) δ 2.36 (s,3H), 2.87-3.10 (m, 4H), 3.71-3.90 (m, 4H), 4.33-4.50 (m, 2H), 6.81-6.91(m, 2H), 7.35-7.46 (m, 3H), 7.47-7.63 (m, 4H), 7.72-7.84 (m, 3H), 9.45(s, 1H).

EXAMPLE 25N-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H and5-bromo-3-methylbenzo[b]thiophene-2-sulfonamide for EXAMPLE 1E inEXAMPLE 1I, except here the purification was done as in EXAMPLE 11B. ¹HNMR (300 MHz, DMSO-d₆) δ 12.60 (v br s, 1H), 9.60 (v br s, 1H), 8.19 (d,1H), 8.05 (d, 1H), 7.80 (m, 3H), 7.70 (dd, 1H), 7.52 (m, 4H), 7.40 (d,2H), 7.36 (m, 1H), 6.92 (d, 2H), 4.38 (br s, 1H), 3.85 (br s, 1H),3.40-2.80 (envelope, 8H), 2.66 (s, 3H).

EXAMPLE 264-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]thien-2-yl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting5-(2-[1,2,4]oxadiazol-3-yl-vinyl)-thiophene-2-sulfonamide for EXAMPLE 1Eand EXAMPLE 4D for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (300 MHz, DMSO-d₆) δ2.73-2.99 (m, 2H), 3.00-3.22 (m, 2H), 3.73-4.03 (m, 4H), 4.23-4.49 (m,2H), 6.89-6.99 (m, 2H), 7.26-7.45 (m, 4H), 7.48-7.58 (m, 4H), 7.61 (d,1H), 7.71-7.83 (m, 5H), 7.83-7.92 (m, 1H), 9.62 (s, 1H).

EXAMPLE 274-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}benzamide

This EXAMPLE was prepared by substituting1-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide for EXAMPLE 1Eand EXAMPLE 4D for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (300 MHz, DMSO-D6) δ2.02-2.09 (m, 3H), 2.29-2.35 (m, 3H), 2.77-2.97 (m, 2H), 2.98-3.17 (m,2H), 3.81-4.00 (m, 6H), 4.28-4.45 (m, 4H), 6.86-6.99 (m, 2H), 7.32-7.44(m, 3H), 7.48-7.60 (m, 4H), 7.71-7.82 (m, 3H), 9.52 (s, 1H), 12.01 (s,1H).

EXAMPLE 285-{[(4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide

This EXAMPLE was prepared by substituting5-(1-ethyl-propylcarbamoyl)-[1,3,4]thiadiazole-2-sulfonamide for EXAMPLE1E and EXAMPLE 4D for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (300 MHz,DMSO-d₆) δ 0.80 (t, 6H), 1.36-1.71 (m, 4H), 2.37-2.45 (m, 1H), 2.84-3.11(m, 4H), 3.44-3.56 (m, 2H), 3.71-3.92 (m, 2H), 4.30-4.46 (m, 2H),6.80-6.95 (m, 2H), 7.29-7.44 (m, 3H), 7.47-7.65 (m, 4H), 7.69-7.89 (m,3H), 9.45 (s, 1H), 12.59-12.83 (m, 1H).

EXAMPLE 294-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting5-chloro-1,3-dimethyl-H-pyrazole-4-sulfonamide for EXAMPLE 1E andEXAMPLE 4D for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (300 MHz. DMSO-d₆) δ2.36 (s, 3H), 2.79-2.98 (m, 2H), 3.00-3.19 (m, 2H), 3.51-3.59 (m, 2H),3.77 (s, 3H), 3.84-4.03 (m, 2H), 4.28-4.56 (m, 2H), 6.86-7.02 (m, 2H),7.30-7.45 (m, 3H), 7.48-7.64 (m, 4H), 7.71-7.88 (m, 3H), 9.53 (s, 1H).

EXAMPLE 304-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl)}-N-[(4-nitro-5-piperidin-1-ylthien-2-yl)sulfonyl]benzamideEXAMPLE 30A 4-nitro-5-(piperidin-1-yl)thiophene-2-sulfonamide

This EXAMPLE was prepared by substituting piperidine for EXAMPLE 1D inEXAMPLE 1E

EXAMPLE 30B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-nitro-5-piperidin-1-ylthien-2-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 30A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 1B. ¹H NMR (500 MHz, DMSO-d₆) δ 11.79 (br s, 1H),7.93 (s, 1H), 7.80 (d, 2H), 7.74 (m, 1H), 7.52 (m, 4H), 7.39 (d, 2H),7.34 (m, 1H), 6.94 (d, 2H), 4.25 (m, 2H), 3.56 (m, 4H), 3.35 (m, 4H),3.25 (m, 2H), 2.91 (m, 2H), 1.7 (m, 4H), 1.61 (m, 2H).

EXAMPLE 314-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamideEXAMPLE 31A 5-(isoxazol-5-yl)furan-2-sulfonamide

This EXAMPLE was prepared by substituting5-(isoxazol-5-yl)furan-2-sulfonyl chloride for2-acetamido-4-methylthiazole-5-sulfonyl chloride in EXAMPLE 11A.

EXAMPLE 31B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H andEXAMPLE 31A for EXAMPLE 1E in EXAMPLE 1I, except here the purificationwas done as in EXAMPLE 11B. ¹H NMR (300 MHz. DMSO-d₆) δ 9.60 (ν br s,1H), 8.76 (d, 1H), 7.80 (d, 2H), 7.75 (m, 1H), 7.55 (m, 4H), 7.40 (d,2H), 7.42 (br s, 1H), 7.36 (m, 2H), 7.96 (d, 1H), 7.92 (d, 2H), 4.38 (brs, 1H), 3.85 (br s, 1H), 3.40-2.80 (envelope, 8H).

EXAMPLE 324-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4D for EXAMPLE 1H and3,5-dimethylisoxazole-4-sulfonamide for EXAMPLE 1E in EXAMPLE 1I, excepthere the purification was done as in EXAMPLE 11B. ¹H NMR (500 MHz,DMSO-d₆) δ 12.33 (br s, 1H), 7.80 (d, 2H), 7.74 (m, 1H), 7.53 (m, 4H),7.40 (m, 2H), 7.34 (m, 1H), 6.94 (d, 2H), 4.27 (m, 2H), 3.84 (m, 2H),3.55 (m, 2H), 3.25 (m, 2H), 2.96 (m, 2H), 2.68 (s, 3H), 2.38 (s, 3H).

EXAMPLE 334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]thien-2-yl}sulfonyl)benzamideEXAMPLE 33A ethyl 2-(41H-indol-5-yloxy)-4-fluorobenzoate

Ethyl 2,4-difluorobenzoate (12.75 g), K₃PO₄ (14.54 g) and5-hydroxyindole (9.12 g) were stirred at 110° C. in diglyme (125 mL) for24 hours. The reaction was cooled and poured into ether. The solutionwas washed three times with 1M NaOH solution, and brine, and dried. Thesolution was then concentrated, and the crude product was poured intohexanes, stirred, and filtered to give the product.

EXAMPLE 33B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL),5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) was added dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried, and condensed togive the product.

EXAMPLE 33C methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 33B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was condensed to give theproduct.

EXAMPLE 33D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 33C (53.8 g) and ether (400 mL),methanol (25 mL) was added slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted byether (3×100 mL). The extracts were dried, and condensed. The crudeproduct was chromatographed on silica gel with 0-30% ethylacetate/hexanes.

EXAMPLE 33E tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl chloride (3.11 mL) was added via syringe to EXAMPLE 33D (10.0 g)and TEA (12.2 mL) in CH₂Cl₂ (300 mL) at 0° C., and the mixture wasstirred for one minute. N-t-butoxycarbonylpiperazine (8.17 g) was addedand the reaction was stirred at room temperature for 24 hours. Thesuspension was washed with brine, dried, and condensed. The crudeproduct was chromatographed on silica gel with 10-20% ethylacetate/hexanes.

EXAMPLE 33F1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 33E (2.0 g) and triethylsilane (0.3 mL) were stirred in 40 mLtrifluoroacetic acid for one hour. The solution was concentrated andtaken up in Na₂CO₃ solution, and the resulting mixture was extractedtwice with CH₂Cl₂. The combined extracts were washed with brine, dried,and concentrated.

EXAMPLE 33G ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 33A (225 mg), EXAMPLE 33F (240 mg), and HK₂PO₄ (131 mg) werestirred in dimethylsulfoxide (4 mL) at 135° C. for 24 hours. Thereaction was diluted with ethyl acetate, washed three times with water,washed with brine, dried, and concentrated. The crude product waschromatographed on silica gel with 30% ethyl acetate/hexanes.

EXAMPLE 33H2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 33G for EXAMPLE 1G inEXAMPLE 1H.

EXAMPLE 33I4-nitro-5-(3-(pyrrolidin-1-yl)propylamino)thiophene-2-sulfonamide

This EXAMPLE was prepared by substituting 1-(3-aminopropyl)pyrrolidinefor EXAMPLE 1D in EXAMPLE 1E

EXAMPLE 33J4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]thien-2-yl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 33I for EXAMPLE 1E andEXAMPLE 33H for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz. DMSO-d₆) δ11.12 (s, 1H), 9.50 (bs, 1H), 9.28 (t, 1H), 7.80 (s, 1H), 7.58 (d, 1H),7.40-7.35 (m, 4H), 7.15 (d, 1H), 7.08 (d, 2H), 6.85 (dd, 1H), 6.71 (dd,1H), 6.37 (t, 1H), 6.24 (d, 1H), 3.52 (m, 4H), 3.35-3.23 (m, 4H), 3.17(m, 4H), 2.97 (m, 4H), 2.18 (t, 2H), 2.00 (m, 8H), 1.84 (m, 2H), 1.44(t, 2H), 0.93 (s, 6H).

EXAMPLE 344-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideEXAMPLE 34A5-(3-(dimethylamino)propylamino)-4-nitrothiophene-2-sulfonamide

This EXAMPLE was prepared by substituting3-(dimethylamino)-1-propylamine for EXAMPLE 1D in EXAMPLE 1E

EXAMPLE 34B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitrothien-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 34A for EXAMPLE 1E andEXAMPLE 33H for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ10.95 (s, 1H), 9.15 (bs, 1H), 7.58 (d, 1H), 7.43 (s, 1H), 7.35-7.27 (m,4H), 7.03 (d, 2H), 7.01 (dd, 1H), 6.74 (dd, 1H), 6.53 (dd, 1H), 6.31 (t,1H), 6.15 (d, 1H), 2.94 (m, 6H), 2.72 (s, 2H), 2.63 (m, 6H), 2.20-2.12(m, 8H), 1.94 (m, 4H), 1.37 (t, 2H), 0.91 (s, 6H).

EXAMPLE 354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitrothien-2-yl}sulfonyl)benzamideEXAMPLE 35A 5-(3-morpholinopropylamino)-4-nitrothiophene-2-sulfonamide

This EXAMPLE was prepared by substituting 3-(4-morpholino)-1-propylaminefor EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 35B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholin-4-ylpropyl)amino]-4-nitrothien-2-yl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 35A for EXAMPLE 1E andEXAMPLE 33H for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz. DMSO-d₆) δ11.04 (s, 1H), 9.45 (bs, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.35-7.30 (m,4H), 7.09 (dd, 1H), 7.04 (d, 2H), 6.80 (dd, 1H), 6.61 (dd, 1H), 6.34 (t,1H), 6.16 (d, 1H), 3.62 (t, 4H), 3.30 (m, 2H), 3.02 (t, 4H), 2.78 (bs,2H), 2.54 (m, 6H), 2.25 (m, 4H), 2.14 (t, 2H), 1.95 (s, 2H), 1.83 (m,2H), 1.38 (t, 2H), 0.91 (s, 6H).

EXAMPLE 36N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitrothien-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidin-1-yl}benzamideEXAMPLE 36A ethyl4-(4-(2-(trifluoromethyl)benzylidene)piperidin-1-yl)benzoate

A suspension of 2-(trifluoromethyl)benzyl triphenylphosphonium bromide(prepared according to the procedure described in J. Chem. Soc. PerkinTrans. I 1995, 18, 2293-2308) (0.737 g) in THF (10 mL) was treated withn-butyllithium (724 μL of a 1.6M solution in hexanes) at 0° C., treatedwith ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to theprocedure described in Synthesis 1981, 606-608, 0.32 g), and graduallywarmed to room temperature overnight. The reaction mixture waspartitioned between ethyl acetate and saturated aqueous NH₄Cl and theaqueous layer was extracted with ethyl acetate (2×). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated. Theresulting residue was purified by silica gel chromatography eluting with10% ethyl acetate in hexanes to give the desired product.

EXAMPLE 36B 4-(4-(2-(trifluoromethyl)benzylidene)piperidin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 36A for EXAMPLE 1G inEXAMPLE 1H.

EXAMPLE 36C N-[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propylamino)-4-nitrothien-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidin-1-yl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 36B for EXAMPLE 1H inEXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (brs, 1H), 8.91 (d, 1H),7.79 (d, 2H), 7.72 (d, 1H), 7.64 (dd, 1H), 7.46 (m, 2H), 7.35 (m, 3H),7.26 (m, 2H), 7.17 (t, 1H), 6.88 (d, 2H), 6.49 (s, 1H), 3.60 (m, 1H),3.25-3.50 (m, 5H), 2.99 (m, 1H), 2.91 (m, 1H), 2.74 (s, 6H), 2.64 (s,6H), 2.44 (m, 2H), 2.27 (m, 2H), 2.11 (m, 2H).

EXAMPLE 374-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(1,1-dioxidotetrahydrothien-3-yl)sulfonyl]benzamideEXAMPLE 37A (4′-chlorobiphenyl-2-yl)methanol

A mixture of 2-iodobenzyl alcohol (11.0 g), 4-chlorophenylbenzeneboronicacid (8.5 g), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (800 mg) inNa₂CO₃ (2M solution, 94 mL) and dioxane (300 mL) was heated to 80° C.for 24 hours. The mixture was cooled, the layers were separated, and theorganic layer was condensed. The resulting residue was purified bysilica gel chromatography eluting with 20% ethyl acetate in hexanes togive the desired product.

EXAMPLE 37B 2-(bromomethyl)-4′-chlorobiphenyl

To a mixture of EXAMPLE 37A (7.9 g) and LiBr (3.45 g) in DMF (100 mL) at0° C. was added PBr₃ (3.77 mL) and the reaction was stirred for 1 hour.The reaction was poured into water (400 mL), and the mixture wasextracted with ether (3×200 mL). The combined ether layers were washedwith 3× water, and brine, dried over Na₂SO₄, and condensed to give thetitle compound.

EXAMPLE 37C [(4′-chloro-1,1′-biphenyl-2-yl)methyl](triphenyl)phosphoniumbromide

A mixture of EXAMPLE 37B (8.05 g) and triphenylphosphine (7.5 g) inxylene (100 mL) was heated to 110° C. for one hour. The reaction wascooled and filtered, and the solid washed with toluene, and vacuum-driedto give the title compound.

EXAMPLE 37D ethyl 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate

Ethyl 4-fluorobenzoate (36.16 g, 215 mmol),1,4-dioxa-8-azaspiro[4.5]decane (35.40 g, 247 mmol), and potassiumcarbonate (29.72 g, 215 mmol) were added to N,N-dimethylacetamide (500mL) and heated to 100° C. for 16 hours. The solution was cooled,filtered, added to 2M HCl and extracted with 50% ethyl acetate (inhexanes). The organics were washed with water, brine, and dried onanhydrous sodium sulfate. The solution was concentrated and purified byflash column chromatography on silica gel with 20% ethyl acetate (inhexanes) increasing to 30% ethyl acetate (in hexanes).

EXAMPLE 37E ethyl 4-(4-oxopiperidin-1-yl)benzoate

EXAMPLE 37D (16.23 g, 55.71 mmol) was dissolved in toluene (85 mL), and1M HCl was added (85 mL). The solution was heated at 95° C. for threehours and cooled. 50% ethyl acetate (in hexanes) was added and thephases were separated. The organic phase was washed with water, thenbrine, and dried on anhydrous sodium sulfate. The solvent was removedand the material used without further purification.

EXAMPLE 37F ethyl4-(4-((4′-chlorobiphenyl-2-yl)methylene)piperidin-1-yl)benzoate

Sodium hydride (60% in mineral oil, 1.617 g, 40.4 mmol) was added todimethylsulfoxide (265 mL) and heated at 80° C. for 30 minutes. EXAMPLE37C was added followed by EXAMPLE 37E while continuing to heat thesolution at 80° C. Heating at 80° C. was continued for 45 minutes. Thesolution was cooled, added to water, and extracted with diethyl etherthree times. The ether extracts were washed with water, then brine, anddried on anhydrous sodium sulfate. The solution was concentrated andpurified by flash column chromatography on silica gel with 10% ethylacetate (in hexanes) increasing to 20% ethyl acetate (in hexanes).

EXAMPLE 37G4-(4-((4′-chlorobiphenyl-2-yl)methylene)piperidin-1-yl)benzoic acid

This EXAMPLE was prepared by substituting EXAMPLE 37F for EXAMPLE 4C inEXAMPLE 4D.

EXAMPLE 37H4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(1,1-dioxidotetrahydrothien-3-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substitutingtetrahydrothiophene-3-sulfonamide 1,1-dioxide for EXAMPLE 1E and EXAMPLE37G for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (d,2H), 7.48 (dt, 2H), 7.42-7.33 (m, 4H), 7.31-7.23 (m, 2H), 6.85 (d, 2H),6.13 (s, 1H), 4.33 (m, 1H), 3.35-3.22 (m, 4H), 3.20-3.06 (m, 4H), 2.30(m, 6H).

EXAMPLE 384-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methylene]piperidin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide for EXAMPLE 1E andEXAMPLE 37G for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ8.09 (d, 1H), 7.90 (s, 1H), 7.77 (d, 2H), 7.58-7.52 (m, 2H), 7.47 (dt,2H), 7.41-7.33 (m, 4H), 7.28 (m, 1H), 6.91 (d, 2H), 6.13 (s, 1H), 3.42(m, 2H), 3.26 (m, 2H), 2.62 (s, 3H), 2.28 (m, 4H).

EXAMPLE 394-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-phenoxybenzamideEXAMPLE 39A ethyl 4-fluoro-2-phenoxybenzoate

This EXAMPLE was prepared by substituting phenol for 5-hydroxyindole inEXAMPLE 33A.

EXAMPLE 39B 4′-chlorobiphenyl-2-carbaldehyde

2-bromobenzaldehyde (25.05 mL, 40.0 g, 216 mmol) was added to toluene(550 mL) and degassed and flushed with nitrogen. 4-chlorophenylboronicacid (43.9 g, 281 mmol), degassed 2M sodium carbonate (757 mL, 1513mmol), and tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.32 mmol)were added. The mixture was refluxed for 2.5 hours, cooled, and thephases were separated. The organic layer was extracted with 2M sodiumcarbonate, and the aqueous layer was back extracted with ethyl ether.The organic portions were combined, dried with brine and then anhydroussodium sulfate. The solution was concentrated and purified by flashcolumn chromatography on silica gel with 3% ethyl acetate (in hexanes)increasing to 10% ethyl acetate (in hexanes).

EXAMPLE 39C tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate

This EXAMPLE was prepared by substituting EXAMPLE 39B for EXAMPLE 7A and1-(tert-butoxycarbonyl)piperazine for methylisopropylamine in EXAMPLE7B.

EXAMPLE 39D 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine

This EXAMPLE was prepared by substituting EXAMPLE 39C for EXAMPLE 33E inEXAMPLE 33F.

EXAMPLE 39E ethyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This EXAMPLE was prepared by substituting EXAMPLE 39A for EXAMPLE 33Aand 39D for EXAMPLE 33F in EXAMPLE 33G.

EXAMPLE 39F4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 39E for EXAMPLE 1G inEXAMPLE 1H.

EXAMPLE 39G4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-phenoxybenzamide

This EXAMPLE was prepared by substituting5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide for EXAMPLE 1E andEXAMPLE 39F for EXAMPLE 1H in EXAMPLE 1I. ¹H NMR (400 MHz, DMSO-d₆) δ8.06 (d, 1H), 7.98 (d, 1H), 7.60-7.34 (m, 9H), 7.27-7.18 (m, 3H), 6.94(t, 1H), 6.83 (d, 2H), 6.75 (dd, 1H), 6.36 (d, 1H), 3.48 (m, 2H), 3.16(bs, 4H), 2.54 (s, 3H), 2.43 (bs, 4H).

EXAMPLE 402-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamideEXAMPLE 40A ethyl 2-(3-chlorophenoxy)-4-fluorobenzoate

Ethyl 2,4-difluorobenzoate (6.0 g), K₃PO₄ (7.5 g) and 3-chlorophenol(4.1 g) were stirred at 110° C. in diglyme (25 mL) for 24 hours. Themixture was cooled and poured into ether. The solution was washed threetimes with 1M NaOH solution, and with brine, and dried. The solution wasthen concentrated. The concentrate was chromatographed on silica gelwith 10% ethyl acetate/hexanes.

EXAMPLE 40B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane-washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoroacetic anhydride (40 mL) was added. The mixture waswarmed to room temperature and stirred for 24 hours. The extract waswashed with brine, dried and concentrated.

EXAMPLE 40C methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 40B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether was added, and the mixture wasfiltered and concentrated.

EXAMPLE 40D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 40C (53.8 g) and ether (400 mL),methanol (25 mL) was added slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The mixture was quenched with 1N HCl withice cooling. The mixture was diluted with water and extracted by ether(3×100 mL). The extracts were dried, and concentrated. The concentratewas chromatographed on silica gel with 0-30% ethyl acetate/hexanes.

EXAMPLE 40E tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl chloride (7.5 mL) was added via syringe to EXAMPLE 40D (29.3 g)and triethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C. and the mixturewas stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was addedand the mixture was stirred at room temperature for 24 hours. Thesuspension was washed with brine, dried, and concentrated. Theconcentrate was chromatographed on silica gel with 10-20% ethylacetate/hexanes.

EXAMPLE 40F1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 40E (3.0 g) and triethylsilane (1 mL) were stirred indichloromethane (30 mL) and trifluoroacetic acid (30 mL) for 2 hours.The mixture was concentrated, taken up in ether and concentrated again.

EXAMPLE 40G ethyl2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 40A (1.2 g), EXAMPLE 40F (1.4 g), and HK₂PO₄ (0.9 g) werestirred in DMSO (2 mL) at 130° C. for 24 hours. The mixture was dilutedwith ethyl acetate, washed three times with water, washed with brine,dried, and concentrated. The concentrate was chromatographed on silicagel with 20% ethyl acetate/hexanes.

EXAMPLE 40H2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 40G (400 mg) was stirred in 12 mL 5:1 dioxane/2M LiOH at 90° C.for 7 hours. The solution was cooled and concentrated. Water was added,and the pH was adjusted to 4 with 1M HCl, and extracted with ethylacetate. The extract was washed with brine, dried (Na₂SO₄), andconcentrated.

EXAMPLE 40I 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (2.9g, prepared by the method of EP142152(A2,A3)) was dissolved in THF (40mL), cooled to 0° C., concentrated, and NH₄OH was added (4.0 mL). Thereaction was stirred cold for 10 minutes, then at room temperature for30 minutes. The supernatant was decanted and the solids partitionedbetween water and CHCl₃/isopropyl alcohol (3/1). The aqueous layer wasextracted twice more with CHCl₃/isopropyl alcohol (3/1). The combinedorganic layers were dried (Na₂SO₄), and concentrated.

EXAMPLE 40J2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide

EXAMPLE 40H (170 mg), EXAMPLE 40I (68 mg),1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (113 mg),and 4-dimethylaminopyridine (72 mg) were stirred in CH₂Cl₂ (3 mL) for 24hours. After concentration and redissolving the mixture inDMSO/methanol, purification was done by preparative HPLC using a C18column, 250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs.0.1% TFA in water. The resultant salt was neutralized by partitioningbetween CHCl₂ and saturated NaHCO₃. ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d,1H), 7.38 (d, 2H), 7.20 (s, 1H), 7.13 (dd, 1H), 7.08 (d, 2H), 6.87 (d,1H), 6.76 (dd, 1H), 6.43 (s, 1H), 6.42 (d, 1H), 6.36 (s, 1H), 3.13 (brs, 4H), 2.80 (br s, 2H), 2.68 (s, 3H), 2.59 (s, 3H), 2.25 (br s, 4H),2.19 (br m, 2H), 1.98 (s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 41A ethyl 4-fluoro-2-(6-fluoro-1H-indol-5-yloxy)benzoate

This EXAMPLE was prepared by substituting 6-fluoro-5-hydroxyindole(prepared by the method of WO02/12227) for 3-chlorophenol in EXAMPLE40A.

EXAMPLE 41B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 41A for EXAMPLE 40A inEXAMPLE 40G.

EXAMPLE 41C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 41B for EXAMPLE 40G inEXAMPLE 40H.

EXAMPLE 41D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl)}piperazin-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 41C for EXAMPLE 40H inEXAMPLE 40J. ¹H NMR (500 MHz. DMSO-d) δ 11.07 (s, 1H), 7.78 (d, 1H),7.36 (d, 2H), 7.30 (m, 1H), 7.24 (d, 1H), 7.20 (s, 1H), 7.08 (d, 3H),6.59 (dd, 1H), 6.30 (s, 1H), 6.05 (s, 1H), 2.95 (br s, 4H), 2.75 (br s,2H), 2.68 (s, 3H), 2.59 (s, 3H), 2.22 (br s, 4H), 2.17 (br m, 2H), 1.95(s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 424-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamideEXAMPLE 42A ethyl 2-(6,7-difluoro-1H-indol-5-yloxy)-4-fluorobenzoate

This EXAMPLE was prepared by substituting 6,7-difluoro-5-hydroxyindole(prepared by the method of WO02/12227) for 3-chlorophenol in EXAMPLE40A.

EXAMPLE 42B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 42A for EXAMPLE 40A inEXAMPLE 40G.

EXAMPLE 42C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 42B for EXAMPLE 40G inEXAMPLE 40H.

EXAMPLE 42D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 42C for EXAMPLE 40H inEXAMPLE 40J. ¹H NMR (500 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.80 (d, 1H),7.33 (d, 2H), 7.31 (s, 1H), 7.17 (s, 1H), 7.03 (d, 2H), 6.70 (d, 1H),6.65 (dd, 1H), 6.35 (m, 1H), 6.19 (s, 1H), 3.00 (br s, 4H), 2.71 (br s,2H), 2.68 (s, 3H), 2.59 (s, 3H), 2.20 (br s, 4H), 2.17 (br m, 2H), 1.95(s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 43 tert-butyl(2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylateEXAMPLE 43A 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 43B 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 43A (24.3 g) in tetrahydrofuran (500 mL) at −78°C. was added 2.5 M n-butyllithium (30.3 mL). After 2 minutes,trimethylborate (11.5 mL) was added, and the mixture was allowed to warmto room temperature over 1 hour. The reaction was poured into water,extracted three times with ethyl acetate, and the combined extracts werewashed with brine and concentrated. The crude product was taken up intetrahydrofuran (200 mL) at 0° C., and 1M aqueous NaOH (69 mL) wasadded, followed by 30% aqueous H₂O₂ (8.43 mL), and the solution wasstirred for 1 hour. Na₂S₂O₃ (10 g) was added, and the pH was adjusted to4-5 with concentrated HCl and solid NaH₂PO₄. The solution was extractedtwice with ethyl acetate, and the combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 5-25% ethyl acetate/hexanes.

EXAMPLE 43C methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 43B (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

EXAMPLE 43D methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 43C (1.55 g), EXAMPLE 33F (2.42 g), and HK₂PO₄(1.42 g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24hours. The reaction was cooled, diluted with ether (400 mL), and washedthree times with 1M NaOH, and brine, and concentrated. The crude productwas chromatographed on silica gel with 10-50° % ethyl acetate/hexanes.

EXAMPLE 43E2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 43D (200 mg) in dioxane (10 mL) and 1M aqueous NaOH (6 mL) at50° C. was stirred for 24 hours. The reaction was cooled, added toNaH₂PO₄ solution, and extracted three times with ethyl acetate. Thecombined extracts were washed with brine, and concentrated to give thepure product.

EXAMPLE 43F 2-chloro-4-methylthiazole-5-sulfonamide

A solution of 2-chloro-4-methylthiazole-5-sulfonyl chloride (1.0 g) inisopropyl alcohol (10 mL) was cooled with an ice-bath. Then, ammoniumhydroxide (2.89 ml) was added slowly. The resulting solution was stirredat ambient temperature overnight. The solution was concentrated, theresidue was mixed with water (10 mL) and extracted with ethyl acetate(2×20 mL). The crude product was purified on a silica gel column elutingwith 60% ethyl acetate-hexane.

EXAMPLE 43G (S)-tert-butyl2-((4-methyl-5-sulfamoylthiazol-2-yloxy)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate (123 mg) in anhydroustetrahydrofuran (5 mL) was added sodium hydride (60% dispersion withmineral oil, 94 mg). The mixture was stirred at room temperature for 30minutes, followed by addition of EXAMPLE 43F (100 mg). The mixture wasstirred at room temperature overnight. The reaction was quenched withwater (15 mL) and extracted with ethyl acetate. The crude product waspurified on a silica gel column eluting with 60% ethyl acetate in hexaneto give the title compound.

EXAMPLE 43H tert-butyl(2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

This example was prepared by substituting EXAMPLE 43E for EXAMPLE 1H andEXAMPLE 43G for EXAMPLE 1E in EXAMPLE 1I. ¹H NMR (500 MHz, pyridine-d₅)δ 13.00 (s, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.68 (d, 1H), 7.67 (t, 1H),7.45 (d, 2H), 7.08 (d, 2H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.50 (dd, 1H),4.52-4.45 (m, 2H), 3.90-3.70 (m, 4H), 3.47 (dt, 1H), 3.07 (m, 4H),2.98-2.84 (m, 2H), 2.77 (s, 2H), 2.76 (s, 3H), 2.26 (m, 2H), 2.14 (m,4H), 1.97 (s, 2H), 1.52 (s, 9H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 44 tert-butyl(2S)-2-{[(5-{[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylateEXAMPLE 44A methy 4-fluoro-2-(3-fluoro-2-nitophenoxy)benzoate

To a solution of methyl 4-fluoro-2-hydroxybenzoate (3.0 g) intetrahydrofuran (65 ml) was added potassium t-butoxide (1.979 g)portionwise. The resulting solution was stirred at ambient temperaturefor 30 minutes and a solution of 1,3-difluoro-2-nitrobenzene (2.338 g)in tetrahydrofuran (15 ml) was added dropwise. After 1 hour the reactionwas heated at reflux for 18 hours. The reaction was quenched with water(10 ml), diluted with brine (75 ml) and extracted with twice methylenechloride (75 ml). The crude product was isolated by concentration andpurified on silica gel, and eluted with a 10, 20, 50% ethyl acetate inhexane step gradient.

EXAMPLE 44B methyl2(3-(bis(4-methoxyphenyl)methylamino)-2-mitrophenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 44A (3.82 g) andbis(4-methoxyphenyl)methanamine (4.51 g) in N-methyl-2-pyrrolidinone(65. ml) was added N-ethyl-N-isopropylpropan-2-amine (4.30 ml) and themixture was heated at 100° C. for 24 hours. The crude product, isolatedby concentration, was purified on silica gel, eluted with a 10, 25, 65%ethyl acetate in hexane step gradient.

EXAMPLE 44C methyl2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 44B (2.76 g) in tetrahydrofuran (125 ml) in astainless steel bottle was added nickel catalyst (2.76 g). The mixturewas stirred for 1 hour under 30 psi of hydrogen at ambient temperature.The mixture was filtered through a nylon membrane to remove the catalystand the title compound was obtained upon evaporation of the solvent(2.54 g).

EXAMPLE 44D methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-fluorobenzoate

To a solution EXAMPLE 44C (1.25 g) in triethyl orthoformate (30 ml) wasadded concentrated hydrochloric acid (0.75 ml). The mixture was stirredfor 18 hours, quenched by the slow addition of 50% saturated sodiumcarbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml).The crude product was isolated by concentration and purified on silicagel, and was eluted with a 25, 50, 70% ethyl acetate in hexane stepgradient.

EXAMPLE 44E methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(piperazin-1-yl)benzoate

A solution of EXAMPLE 44D (500 mg) and piperazine (420 mg) indimethylsulfoxide (9 ml) was heated at 100° C. for 3 hours. The crudeproduct was isolated by concentration and, following an aqueous work up,was purified on silica gel, and was eluted with a 5, 10% methanol inmethylene chloride step gradient.

EXAMPLE 44F 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 33D for EXAMPLE 8C inEXAMPLE 8D.

EXAMPLE 44G methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 44E (430 mg) and EXAMPLE 44F (259 mg) indichloromethane (13 ml) was added sodium triacetoxyborohydride (323 mg)portionwise. After stirring 42 hours, the reaction was quenched slowlywith saturated aqueous sodium bicarbonate solution (80 ml) and extractedwith methylene chloride (2×70 ml). The crude product was isolated byconcentration and purified on silica gel, and was eluted with a 0, 2,10% methanol in methylene chloride step gradient.

EXAMPLE 44H2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 44G (545 mg) in a mixture of methanol (7.50 ml)and tetrahydrofuran (7.50 ml) was added a solution of sodium hydroxide(269 mg) in water (3.0 ml). The reaction mixture was heated at 50° C.for 18 hours and was concentrated. The residue was mixed with water (100ml), the pH was adjusted to ca. 7 with 1M aqueous hydrochloric acid, andthe mixture was extracted with 10% methanol in methylene chloride (10×50ml).

EXAMPLE 44I8-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-11H-benz[b]imidazo[1,5,4-ef][1,5]benzoxazepin-11-one

A solution of EXAMPLE 44G (4.5 g) in anhydrous dichloromethane (100 ml)was cooled in an ice bath and catalytic N,N-dimethylformamide was added.This was followed by the dropwise addition of a solution of oxalyldichloride (1.231 ml) in anhydrous methylene chloride (5 ml). The icebath was removed and the reaction stirred for 1 hour. The reaction wasquenched by the addition of ice (ca. 150 ml) and saturated sodiumbicarbonate solution (100 ml). The mixture further diluted withsaturated aqueous sodium bicarbonate solution (200 ml) and methylenechloride (200 ml). The crude product was isolated by concentration ofthe organic layer and the residue was purified on silica gel, elutingwith a 0, 10, 25, 100% ethyl acetate in methylene chloride stepgradient.

EXAMPLE 44J tert-butyl(2S)-2-{[(5-{[2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

To a solution of EXAMPLE 43G (35 mg) in anhydrous tetrahydrofuran (4 mL)was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (19.95 μl).The mixture was stirred at room temperature for 30 minutes. EXAMPLE 44I(49.2 mg) was added and the solution was stirred overnight at roomtemperature. The solution was concentrated. The residue was re-dissolvedin dimethylsulfoxide-methanol and was purified on a HPLC (Waters LC4000Prep system, C18 column) using 10 mM of ammonium acetate bufferedwater-acetonitrile as the mobile phase. ¹H NMR (500 MHz, pyridine-d₅) δ8.55 (s, 1H), 8.00 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.27 (t, 1H),7.22 (m, 2H), 7.07 (d, 2H), 6.73 (d, 1H), 6.71 (dd, 1H), 4.52-4.45 (m,2H), 3.90-3.70 (m, 4H), 3.47 (dt, 1H), 3.04 (m, 4H), 2.98-2.83 (m, 2H),2.77 (s, 2H), 2.76 (s, 3H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H),1.52 (s, 9H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 454-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideEXAMPLE 45A2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-4-methylthiazole-5-sulfonamide

This example was prepared by substituting(4-fluorotetrahydro-2H-pyran-4-yl)methanol for (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate in EXAMPLE 43G.

EXAMPLE 45B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 43E for EXAMPLE 1H andEXAMPLE 45A for EXAMPLE 1E in EXAMPLE 1I. ¹H NMR (500 MHz, pyridine-d₅)δ 13.01 (s, 1H), 8.43 (d, 1H), 8.15 (d, 1H), 7.70 (d, 1H), 7.65 (t, 1H),7.45 (d, 2H), 7.08 (d, 2H), 6.77 (dd, 1H), 6.55 (d, 1H), 6.50 (dd, 1H),4.52 (dd, 2H), 3.83-3.79 (m, 2H), 3.72-3.70 (m, 2H), 3.07 (m, 4H), 2.80(s, 3H), 2.78 (s, 2H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H),1.82-1.75 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 462-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({2-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 45A for EXAMPLE 43G inEXAMPLE 44J. ¹H NMR (500 MHz, pyridine-d₅) δ 8.56 (s, 1H), 8.02 (d, 1H),7.53 (d, 1H), 7.44 (d, 2H), 7.27 (t, 1H), 7.21 (m, 2H), 7.08 (d, 2H),6.74 (d, 1H), 6.71 (dd, 1H), 4.54 (dd, 2H), 3.84-3.79 (m, 2H), 3.73-3.70(m, 2H), 3.05 (m, 4H), 2.79 (s, 3H), 2.78 (s, 2H), 2.26 (m, 2H), 2.16(m, 4H), 1.98 (s, 2H), 1.82-1.75 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 47 (S)-tert-butyl2-((5-(N-(2-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-4-methylthiazol-2-yloxy)methyl)morpholine-4-carboxylateEXAMPLE 47A tert-butyl 4-hydroxy-1H-indazole-1-carboxylate andtert-butyl 4-hydroxy-2H-indazole-2-carboxylate

4-Hydroxyindazole (3.94 g) was added to tetrahydrofuran (250 mL) and themixture was cooled to 0° C. using an ice bath. Sodium hydride (60%dispersion in mineral oil, 1.23 g) was added, and the mixture wasstirred at 0° C. for five minutes. The solution was allowed to warm toroom temperature and was stirred for an additional 20 minutes. Thesolution was again cooled to 0° C. using an ice bath, andtert-butyldimethylchlorosilane (4.65 g) was added. The solution wasallowed to warm to room temperature and stirred for 16 hours. Solventvolume was reduced under vacuum, the residue was vacuum filtered over apad of silica gel and washed with ethyl acetate. The combined solutionswere concentrated. The resulting residue was mixed with acetonitrile(200 mL), di-tert-butyl dicarbonate (7.06 g), and4-(dimethylamino)pyridine (0.359 g). The solution was stirred at roomtemperature for three hours, and the solvent was removed under vacuum.To the residue was added tetrahydrofuran (200 mL) and tetrabutylammoniumfluoride (1M in tetrahydrofuran, 82 mL). After stirring at roomtemperature for four days, the solvent was removed under vacuum, and theresidue was taken up in ethyl acetate. The solution was washed withsaturated aqueous ammonium chloride and brine, then dried over anhydroussodium sulfate. The solution was filtered over silica gel, and thesolvent was removed under vacuum to give the title compounds.

EXAMPLE 47B 4-Fluoro-2-(1H-indazol-4-yloxy)-benzoic acid methyl ester

To a solution of EXAMPLE 47A (5.56 g) in diglyme (200 mL) was addedpotassium tert-butoxide (1M in tetrahydrofuran, 30.8 mL). The solutionwas stirred at room temperature for 15 minutes. Methyl2,4-difluorobenzoate was added and the solution was stirred at 115° C.for 16 hours. The solution was cooled and the solvent removed undervacuum. The residue was taken up in dichloromethane (100 mL), andtrifluoroacetic acid (22.6 mL) was added. The solution was stirred atroom temperature for 16 hours. The solvent was removed under vacuum, theresidue was taken up in ethyl acetate and washed with a saturate aqueoussodium bicarbonate solution, and the organic layer dried with anhydroussodium sulfate. The material was purified by flash column chromatographyon silica gel using 30% ethyl acetate (hexanes) increasing to 40% ethylacetate (hexanes).

EXAMPLE 47C 2-(1H-Indazol-4-yloxy)-4-piperazin-1-yl-benzoic acid methylester

This example was prepared by substituting EXAMPLE 47B for EXAMPLE 44D inEXAMPLE 44E.

EXAMPLE 47D4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(1H-indazol-4-yloxy)-benzoicacid methyl ester

This example was prepared by substituting EXAMPLE 47C for EXAMPLE 44E inEXAMPLE 44G.

EXAMPLE 47E2-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 47D for EXAMPLE 44G inEXAMPLE 44H.

EXAMPLE 47F (S)-tert-butyl2-((5-(N-(2-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-4-methylthiazol-2-yloxy)methyl)morpholine-4-carboxylate

This example was prepared by substituting EXAMPLE 47E for EXAMPLE 1H andEXAMPLE 43G for EXAMPLE 1E in EXAMPLE 1I. ¹H NMR (500 MHz, pyridine-d₅)δ 8.36 (s, 1H), 8.11 (d, 1H), 7.47 (d, 2H), 7.38 (d, 1H), 7.22 (m, 2H),7.11 (d, 2H), 6.88-6.80 (m, 2H), 6.62 (d, 1H), 4.52-4.45 (m, 2H),3.90-3.70 (m, 4H), 3.45 (dt, 1H), 3.15 (m, 4H), 2.98-2.83 (m, 2H), 2.82(s, 2H), 2.63 (s, 3H), 2.30 (m, 2H), 2.23 (m, 4H), 1.99 (s, 2H), 1.52(s, 9H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 482-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-4-methylthiazol-5-ylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 47E for EXAMPLE 1H andEXAMPLE 45A for EXAMPLE 1E in EXAMPLE 1I. ¹H NMR (500 MHz, pyridine-d₅)δ 8.36 (s, 1H), 8.14 (d, 1H), 7.47 (d, 2H), 7.38 (d, 1H), 7.22 (m, 2H),7.11 (d, 2H), 6.88-6.80 (m, 2H), 6.62 (d, 1H), 4.52 (dd, 2H), 3.84-3.78(m, 2H), 3.73-3.70 (dt, 2H), 3.15 (m, 4H), 2.82 (s, 2H), 2.67 (s, 3H),2.30 (m, 2H), 2.23 (m, 4H), 1.99 (s, 2H), 1.82-1.75 (m, 4H), 1.41 (t,2H), 0.96 (s, 6H).

What is claimed is:
 1. A compound, or therapeutically acceptable saltthereof, wherein the compound isN-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}benzamide;and4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide.2. A composition comprising an excipient and a therapeutically effectiveamount of the compound or therapeutically acceptable salt of claim 1.